Submissions for variant NM_005912.2(MC4R):c.110A>T (p.Asp37Val)

gnomAD frequency: 0.00013  dbSNP: rs13447325

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000435394	SCV000513546	likely benign	not specified	2016-05-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000015395	SCV001280932	uncertain significance	Obesity	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262822	SCV001440830	likely benign	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001699179	SCV004297610	uncertain significance	not provided	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 37 of the MC4R protein (p.Asp37Val). This variant is present in population databases (rs13447325, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features associated with MC4R-related obesity (PMID: 12970296). ClinVar contains an entry for this variant (Variation ID: 14319). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect MC4R function (PMID: 16752916). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015395	SCV000052812	not provided	Obesity	2015-10-02	no assertion provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000015395	SCV000692295	uncertain significance	Obesity	2017-11-22	no assertion criteria provided	clinical testing	present with c.105C>A in two patients, phase not known
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000015395	SCV000733801	likely benign	Obesity		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699179	SCV001924585	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001699179	SCV001926982	likely benign	not provided		no assertion criteria provided	clinical testing