Submissions for variant NM_000256.3(MYBPC3):c.2963G>T (p.Gly988Val)

dbSNP: rs727504942

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156342	SCV000206060	uncertain significance	not specified	2014-01-30	criteria provided, single submitter	clinical testing	The Gly988Val variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational analyses (bio chemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) su ggest that the Gly988Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of the Gly988Val variant.
Color Diagnostics, LLC DBA Color Health	RCV001179109	SCV001343709	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 988 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has not been identified 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	RCV001850156	SCV002224252	uncertain significance	Hypertrophic cardiomyopathy	2023-05-05	criteria provided, single submitter	clinical testing	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 disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 179550). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 988 of the MYBPC3 protein (p.Gly988Val).
Ambry Genetics	RCV002433686	SCV002751535	uncertain significance	Cardiovascular phenotype	2023-09-06	criteria provided, single submitter	clinical testing	The p.G988V variant (also known as c.2963G>T), located in coding exon 28 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 2963. The glycine at codon 988 is replaced by valine, an amino acid with dissimilar properties. Another variant affecting this codon (p.G988R, c.2962G>A) has been detected in a hypertrophic cardiomyopathy cohort (Inagaki N et al. J. Hum. Genet., 2018 Dec;63:1273-1276). This amino acid position is well 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	RCV001179109	SCV003838936	uncertain significance	Cardiomyopathy	2021-08-11	criteria provided, single submitter	clinical testing