Submissions for variant NM_000256.3(MYBPC3):c.1544A>G (p.Asn515Ser)

gnomAD frequency: 0.00039  dbSNP: rs181834806

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151126	SCV000052947	likely benign	not specified	2021-07-06	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.1544A>G (p.Asn515Ser) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consistently, a recent study evaluating the impact of this variant on protein destabilization as estimated by a software that estimates changes in free energy upon mutation from emperically and statistically derived energy functions (FoldX), reported a non-pathogenic outcome (Suay-Corredara_2021). The variant allele was found at a frequency of 0.0001 in 250110 control chromosomes, predominantly at a frequency of 0.0015 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1544A>G has been reported in the literature in individuals who did not meet the diagnostic criteria for Hypertrophic Cardiomyopathy (example Bick_2012) and as a VUS in settings of multigene panel testing in cohorts of patients with dilated cardiomyopathy (DCM) (example, Verdonschot_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3, VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151126	SCV000198903	uncertain significance	not specified	2012-07-17	criteria provided, single submitter	clinical testing	The Asn515Ser variant in MYBPC3 has been identified in 3/4338 African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs181834806). This frequency is too low to rul e out a role in disease. Our laboratory has detected this variant in 3 individua ls (1 adult individual with HCM and 2 individuals with early onset HCM or HCM + additional congenital heart defects). Of these, 2 individuals were of Black ance stry, which is consistent with the above results by the NHLBI Exome Sequencing P roject (see above). Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein. However, asparagine (Asn) at position 515 is highly conserved across evolutionarily distant species, increasing the likeliho od that an amino acid change would not be tolerated. In summary, additional info rmation is needed to fully assess the clinical significance of this variant.
GeneDx	RCV001719700	SCV000207986	likely benign	not provided	2019-10-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22763267, 22958901, 24510615, 32880476)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469629	SCV000558164	likely benign	Hypertrophic cardiomyopathy	2024-01-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617682	SCV000736702	benign	Cardiovascular phenotype	2021-09-03	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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755680	SCV000883089	uncertain significance	Left ventricular noncompaction 10	2018-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777739	SCV000913699	likely benign	Cardiomyopathy	2018-10-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000755680	SCV001259956	likely benign	Left ventricular noncompaction 10	2019-01-21	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001103227	SCV001259957	likely benign	Hypertrophic cardiomyopathy 4	2019-01-21	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001719700	SCV002049749	likely benign	not provided	2021-07-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777739	SCV003838278	benign	Cardiomyopathy	2022-05-16	criteria provided, single submitter	clinical testing