Submissions for variant NM_000256.3(MYBPC3):c.649A>G (p.Ser217Gly)

gnomAD frequency: 0.00076  dbSNP: rs138753870

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172559	SCV000051402	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035656	SCV000059307	benign	not specified	2015-05-20	criteria provided, single submitter	clinical testing	p.Ser217Gly in exon 5 of MYBPC3: This variant is not expected to have clinical s ignificance because it has been identified in 1.2% (177/14558) of South Asian ch romosomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org; dbSNP rs138753870).
GeneDx	RCV000172559	SCV000208236	benign	not provided	2021-09-20	criteria provided, single submitter	clinical testing	Reported in ClinVar as a benign and likely benign variant by other clinical laboratories (ClinVar Variant ID# 42780; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22763267, 19632136, 23299917, 22464770, 24503780, 25524337, 24119082, 22958901, 22361390, 21750094, 25351510, 26656175, 27650965, 27600940, 28416588, 29121657, 29032884)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082031	SCV000261419	benign	Hypertrophic cardiomyopathy	2024-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618826	SCV000736843	benign	Cardiovascular phenotype	2016-05-17	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035656	SCV000748014	likely benign	not specified	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771156	SCV000903002	benign	Cardiomyopathy	2018-03-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001105224	SCV001262155	benign	Left ventricular noncompaction 10	2018-06-04	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001105225	SCV001262156	uncertain significance	Hypertrophic cardiomyopathy 4	2018-06-04	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035656	SCV001363316	benign	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.649A>G (p.Ser217Gly) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 240264 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.649A>G has been reported in the literature in individuals affected with affected with hypertrophic- or dilated cardiomyopathy, however without strong evidence for causality (e.g. Roberts_2009, Millat_2010, Ogorodnikova_2011, Mestroni_2010, Lakdawala_2012, Merlo_2013, Pugh_2014). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Additionally, Lakdawala_2012 reported that this variant did not segregate with the disease in one family. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.2827C>T (p.Arg943X) in an internal sample; MYH7 c.1357C>T, (p.Arg453Cys) in Roberts_2009), providing supporting evidence for a benign role. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (5x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000172559	SCV002497122	benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	MYBPC3: BP4, BS1, BS2
Dept of Medical Biology, Uskudar University	RCV003318339	SCV004022096	benign	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, BS2, PP3
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000172559	SCV000280276	likely benign	not provided	2016-03-01	no assertion criteria provided	provider interpretation	reclassified based on 2015 re-review. Data from that re-review is summarized in DOI: 10.1161/CIRCGENETICS.116.001700.
Cohesion Phenomics	RCV001082031	SCV003800600	benign	Hypertrophic cardiomyopathy	2022-10-10	no assertion criteria provided	clinical testing
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	RCV001082031	SCV005373758	pathogenic	Hypertrophic cardiomyopathy		no assertion criteria provided	research