Submissions for variant NM_000256.3(MYBPC3):c.2980C>T (p.Leu994Phe)

gnomAD frequency: 0.00019  dbSNP: rs375776406

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158202	SCV000208137	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Identified in a father and son with hypertrophic cardiomyopathy; however, these two individuals also harbored a pathogenic variant in the MYH7 gene (Burns et al., 2017); Identified in a cohort of individuals with sudden unexplained deaths, however, no additional clinical information was provided, and it is unclear if this individual had variants identified in other genes (Lin et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24510615, 28790153, 29247119, 22958901)
CSER _CC_NCGL, University of Washington	RCV000211436	SCV000212191	uncertain significance	Hypertrophic cardiomyopathy	2015-03-11	criteria provided, single submitter	research
Invitae	RCV000211436	SCV000546445	uncertain significance	Hypertrophic cardiomyopathy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 994 of the MYBPC3 protein (p.Leu994Phe). This variant is present in population databases (rs375776406, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or suffered sudden unexplained death (PMID: 28790153, 29247119). ClinVar contains an entry for this variant (Variation ID: 180992). 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.
Illumina Laboratory Services, Illumina	RCV001103017	SCV001259726	uncertain significance	Hypertrophic cardiomyopathy 4	2018-01-26	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001103018	SCV001259727	benign	Left ventricular noncompaction 10	2018-01-26	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170191	SCV001332742	uncertain significance	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170191	SCV001354083	uncertain significance	Cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 994 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 28790153); this individual also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype. This variant has also been reported in a cohort of individuals affected with sudden unexplained death (PMID: 29247119) and in one individual affected with pediatric dilated cardiomyopathy (PMID: 34935411). This variant has been identified in 19/224572 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	RCV002433696	SCV002746289	uncertain significance	Cardiovascular phenotype	2023-07-10	criteria provided, single submitter	clinical testing	The p.L994F variant (also known as c.2980C>T), located in coding exon 28 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2980. The leucine at codon 994 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been described in hypertrophic cardiomyopathy (HCM) and sudden death cohorts, including some cases with additional cardiac variants also detected (Bagnall RD et al. N Engl J Med, 2016 Jun;374:2441-52; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:). This alteration has also been reported in a pediatric dilated cardiomyopathy (DCM) cohort (Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854). This variant has also been reported in one control subject from a cardiac genetic testing study and in two participants from the Framingham Heart Study/Jackson Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001103017	SCV004047888	uncertain significance	Hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing	The missense c.2980C>T (p.Leu994Phe) Variant in MYBPC3 gene has been reported in heterozygous state individual(s) with hypertrophic cardiomyopathy(Lin, Ying et al.,2017). The amino acid Leu at position 994 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties.The variant is 0.008% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes This variant has been reported to the ClinVar database as Uncertain significance/ Benign. The amino acid change p.Leu994Phe in MYBPC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The available evidence is currently insufficient to determine the role of this variant in disease. For these reasons, this variant has been classified as Uncertain Significance.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000211436	SCV001430814	uncertain significance	Hypertrophic cardiomyopathy	2019-06-03	no assertion criteria provided	research	The MYBPC3 Leu994Phe variant has been reported in 2 healthy individuals in the Framingham/Jackson Heart Study (Bick AG, et al., 2012) and is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.00008. We have identified this variant in 2 probands. The first, a SCD case with no determined cause on post mortem, who harboured a RYR2 (Gly3225Ser) variant (Bagnall RD, et al., 2016). The second, a HCM proband, who also harbours another variant (MYH7 Arg652Gly), both variants segregate with an affected first-degree family member (Burns et al., 2017). Computational tools are in agreement and predict a deleterious effect. In summary, the variant has been identified in 2 healthy individuals and is found to segregate with a rare variant in our family. We therefore classify MYBPC3 Leu994Phe as a variant of "uncertain significance".