Submissions for variant NM_000256.3(MYBPC3):c.2849C>T (p.Ala950Val)

dbSNP: rs730880577

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158190	SCV000208125	uncertain significance	not provided	2017-02-03	criteria provided, single submitter	clinical testing	This variant is dentoed p.Ala950Val (GCA>GTA): c.2849 C>T in exon 27 of the MYBPC3 gene (NM_000256.3). The A950V variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The A950V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts A950V is probably damaging to the protein structure/function. Splice algorithms also predict A950V may affect splicing, creating a cryptic splice donor site. Mutations in nearby residues (R943Q, T957S, T958I) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the A950V variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in HCM panel(s).
Ambry Genetics	RCV000619159	SCV000735856	uncertain significance	Cardiovascular phenotype	2022-08-30	criteria provided, single submitter	clinical testing	The p.A950V variant (also known as c.2849C>T), located in coding exon 27 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2849. The alanine at codon 950 is replaced by valine, an amino acid with similar properties. This alteration has detected in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited, and reported cases may overlap (Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-600; Helms AS et al. Circ Genom Precis Med. 2020 10;13(5):396-405; Harper AR et al. Nat Genet. 2021 02;53(2):135-142). This variant has also been detected in exome cohorts; however, clinical detail was limited (Kars ME et al. Proc Natl Acad Sci U S A. 2021 09;118(36); Park J et al. Nat Med. 2021 01;27(1):66-72). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170196	SCV001332748	uncertain significance	Cardiomyopathy	2019-03-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170196	SCV001346741	uncertain significance	Cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 950 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with hypertrophic cardiomyopathy (PMID: 25524337, 33495597, 33782553). This variant has been identified in 1/243916 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.
Invitae	RCV001246212	SCV001419553	uncertain significance	Hypertrophic cardiomyopathy	2023-06-23	criteria provided, single submitter	clinical testing	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 180985). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25524337, 33782553). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 950 of the MYBPC3 protein (p.Ala950Val).