In Autosomal Dominant Inheritance Asp Detail Id

In Autosomal Dominant Inheritance Asp Detail Id

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MedGen
National Center for Biotechnology Information

Format Full Report Summary (Text) Summary (XML)
MedGen UID: 141047 • Concept ID: C0443147 • Genetic Function; Intellectual Product
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele. [from HPO ]
Sharma A,
Bosman LP,
Tichnell C,
Nanavati J,
Murray B,
Nonyane BAS,
Tandri H,
Calkins H,
James CA
Circ Genom Precis Med
2022 Jun;15(3):e003530.
Epub 2022 May 17
doi: 10.1161/CIRCGEN.121.003530.
PMID: 35579515
Cortés-Martín J,
Díaz-Rodríguez L,
Piqueras-Sola B,
Rodríguez-Blanque R,
Bermejo-Fernández A,
Sánchez-García JC
Int J Environ Res Public Health
2020 Aug 25;17(17)
doi: 10.3390/ijerph17176174.
PMID: 32854429 Free PMC Article
Waung MW,
Taylor A,
Qualmann KJ,
Burish MJ
JAMA Neurol
2020 Jul 1;77(7):887-896.
doi: 10.1001/jamaneurol.2020.0682.
PMID: 32310255 Free PMC Article
Gasser S,
Reichenspurner H,
Girdauskas E
BMC Cardiovasc Disord
2018 Feb 27;18(1):41.
doi: 10.1186/s12872-018-0755-y.
PMID: 29486707 Free PMC Article
Berciano J,
García A,
Gallardo E,
Peeters K,
Pelayo-Negro AL,
Álvarez-Paradelo S,
Gazulla J,
Martínez-Tames M,
Infante J,
Jordanova A
J Neurol
2017 Aug;264(8):1655-1677.
Epub 2017 Mar 31
doi: 10.1007/s00415-017-8474-3.
PMID: 28364294

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Autosomal dominant; Autosomal Dominant
Autosomal dominant inheritance (263681008); Autosomal dominant (263681008); AD - Autosomal dominant (263681008)

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BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Submitted interpretations and evidence

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Allele origin:

unknown

Accession: SCV001984875.1
First in ClinVar: Oct 30, 2021
Last updated: Oct 30, 2021

PubMed:

14633860 ‚

20462274 ‚

21719532 ‚

23146882 ‚

31002796 ‚

25332687

The variant c.268G>A (p.(Asp90Asn)) in exon 1 of the MC4R-gene is not found in the gnomAD database, it affects a highly conserved nucleotide a highly … (more)
The variant c.268G>A (p.(Asp90Asn)) in exon 1 of the MC4R-gene is not found in the gnomAD database, it affects a highly conserved nucleotide a highly conserved amino acid within a protein domain and there is a small physicochemical difference between Asp and Asn. This variant was found in an affected patient with severe early onset obesity in our clinic and has been described in the literature (PMID: 14633860). Functional studies revealed a damaging effect of the variant on protein function (PMID: 20462274; 21719532; 23146882; 31002796; 25332687). This variant has a pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs no benign predictions. ACMG criteria used for classification: PM1, PM2, PS3, PP2, PP3, PP5. (less)
Childhood-onset truncal obesity (present)

The variant c.268G>A (p.(Asp90Asn)) in exon 1 of the MC4R-gene is not found in the gnomAD database, it affects a highly conserved nucleotide a highly conserved amino acid within a protein domain and there is a small physicochemical difference between Asp and Asn. This variant was found in an affected patient with severe early onset obesity in our clinic and has been described in the literature (PMID: 14633860). Functional studies revealed a damaging effect of the variant on protein function (PMID: 20462274; 21719532; 23146882; 31002796; 25332687). This variant has a pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs no benign predictions. ACMG criteria used for classification: PM1, PM2, PS3, PP2, PP3, PP5.

Functional evidence

Help

The variant c.268G>A (p.(Asp90Asn)) in exon 1 of the MC4R-gene is not found in the gnomAD database, it affects a highly conserved nucleotide a highly conserved amino acid within a protein domain and there is a small physicochemical difference between Asp and Asn. This variant was found in an affected patient with severe early onset obesity in our clinic and has been described in the literature (PMID: 14633860). Functional studies revealed a damaging effect of the variant on protein function (PMID: 20462274; 21719532; 23146882; 31002796; 25332687). This variant has a pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs no benign predictions. ACMG criteria used for classification: PM1, PM2, PS3, PP2, PP3, PP5.

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NM_005912.3:c.268G>A

MANE Select

criteria provided, single submitter
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity.

Defect in MAPK signaling as a cause for monogenic obesity caused by inactivating mutations in the melanocortin-4 receptor gene.

International journal of biological sciences

Clinical and functional relevance of melanocortin-4 receptor variants in obese German children.

The cytosolic chaperone Hsc70 promotes traffic to the cell surface of intracellular retained melanocortin-4 receptor mutants.

Molecular endocrinology (Baltimore, Md.)

Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist.

Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization.

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ClinVar Genomic variation as it relates to human health

Search ClinVar

Search ClinVar

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Clinical significance
HGVS expressions
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Data dictionary

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Linking to ClinVar

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Assertion criteria
Expert panels and practice guidelines

Statistics
List of submitters
Submitting groups

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Overview

How to search ClinVar
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Submitted interpretations and evidence

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Allele origin:

germline

FDA Recognized Database

Accession: SCV001960945.1
First in ClinVar: Oct 08, 2021
Last updated: Oct 08, 2021

NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PM2, PP3 and PP4) as defined by the ClinGen … (more)
NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria published in PMID: 7573037. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL: 0,939. PP4 - Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria for FH published in PMID: 7573037. (less)

Allele origin:

germline

Accession: SCV000296027.2
First in ClinVar: Jul 29, 2016
Last updated: May 30, 2018

PubMed:

7573037

Number of individuals with the variant : 1

Allele origin:

germline

Accession: SCV001733662.1
First in ClinVar: Jun 19, 2021
Last updated: Jun 19, 2021

This missense variant (also known as p.Gly823Asp in the mature protein and as FH-Turku) replaces glycine with aspartic acid at codon 844 in the cytoplasmic … (more)
This missense variant (also known as p.Gly823Asp in the mature protein and as FH-Turku) replaces glycine with aspartic acid at codon 844 in the cytoplasmic domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the variant interferes with the basolateral sorting of LDLR with the effect that the protein was mis-targeted to the apical surface of the cell (PMID: 11389828). As a result, binding, internalization and degradation of LDL particles is significantly reduced (PMID: 7573037). Expression of the mutant protein failed to correct hypercholesterolemia in LDLR-deficient mice (PMID: 11389828). This variant has been reported in over ten unrelated individuals affected with familial hypercholesterolemia (PMID: 7573037). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)

Allele origin:

germli
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In Autosomal Dominant Inheritance Asp Detail Id

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