Submissions for variant NM_000256.3(MYBPC3):c.3343G>A (p.Val1115Ile)

gnomAD frequency: 0.00003  dbSNP: rs531189495

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000475681	SCV000546455	uncertain significance	Hypertrophic cardiomyopathy	2023-03-30	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. 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: 407323). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 28356264, 33782553). This variant is present in population databases (rs531189495, gnomAD 0.007%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1115 of the MYBPC3 protein (p.Val1115Ile).
Mendelics	RCV000988536	SCV001138288	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181372	SCV001346505	uncertain significance	Cardiomyopathy	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1115 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 individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 28356264, 32841044). This variant has been identified in 3/240324 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.
Ambry Genetics	RCV002323704	SCV002606653	uncertain significance	Cardiovascular phenotype	2023-02-16	criteria provided, single submitter	clinical testing	The p.V1115I variant (also known as c.3343G>A), located in coding exon 31 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3343. The valine at codon 1115 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been detected in individuals reported to have hypertrophic cardiomyopathy (Erdmann J et al. J Am Coll Cardiol, 2001 Aug;38:322-30; Erdmann J et al. Clin Genet, 2003 Oct;64:339-49; G&oacute;mez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405). 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.
GeneDx	RCV002469153	SCV002765561	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Identified in a patient with HCM in published literature (Erdmann et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33782553, 12974739, 11499719)