Submissions for variant NM_000256.3(MYBPC3):c.2077G>T (p.Ala693Ser)

dbSNP: rs771753579

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779062	SCV000915528	uncertain significance	Hypertrophic cardiomyopathy 4	2018-12-14	criteria provided, single submitter	clinical testing	The MYBPC3 c.2077G>T (p.Arg693Ser) missense variant has been reported in two studies in which it was identified in at least one individual with hypertrophic cardiomyopathy in a compound heterozygous state with a second missense variant (Olivotto et al. 2008; Olivotto et al. 2011). Olivotto et al. (2011) also identified the variant in an individual who carried two other variants in MYBPC3 but it is unclear if this individual is the same individual reported in Olivotto et al. (2008). The p.Arg693Ser variant is absent from 300 controls but is reported at a frequency of 0.000209 in the Latino population of the Genome Aggregation Database. The residue is conserved. Based on the limited evidence, the p.Arg693Ser is classified as a variant of unknown significance for hypertrophic cardiomyopathy.
Invitae	RCV001220265	SCV001392245	uncertain significance	Hypertrophic cardiomyopathy	2022-04-12	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. ClinVar contains an entry for this variant (Variation ID: 632160). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 693 of the MYBPC3 protein (p.Ala693Ser). This variant is present in population databases (rs771753579, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 18533079, 21835320, 28790153, 33782553).
Color Diagnostics, LLC DBA Color Health	RCV001525936	SCV001736151	uncertain significance	Cardiomyopathy	2023-09-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 693 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 18533079, 21835320, 25524337, 32841044, 33782553). This individual also carried another pathogenic variant in the MYBPC3 gene (PMID: 21835320). This variant has been identified in 14/249134 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV002269311	SCV002552589	uncertain significance	not provided	2022-07-05	criteria provided, single submitter	clinical testing	Identified in one patient with HCM who also harbored a second variant in the MYBPC3 gene (Olivotto et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 33782553, 18533079)
Fulgent Genetics, Fulgent Genetics	RCV002493424	SCV002786306	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-09-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003166065	SCV003911266	likely benign	Cardiovascular phenotype	2022-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.