Submissions for variant NM_000256.3(MYBPC3):c.1633C>A (p.Leu545Met)

gnomAD frequency: 0.00015  dbSNP: rs377163678

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151120	SCV000198890	uncertain significance	not specified	2013-12-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Leu545Met varia nt in MYBPC3 has been reported in 1 individual with HCM, but it was also present in 1% (2/200) control chromosomes (Van Dreist 2004). It has also been identifie d in 1/4172 African American chromosomes by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS/; dbSNP rs377163678). Computational analyses (b iochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest tha t this variant may impact the normal function of the protein, though this inform ation is not conclusively predictive. Additional information is needed to fully assess the clinical significance of the Leu545Met variant.
GeneDx	RCV000766337	SCV000208042	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21310275, 28166811, 15519027)
Ambry Genetics	RCV000621152	SCV000735940	likely benign	Cardiovascular phenotype	2022-11-23	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.
Invitae	RCV000686894	SCV000814435	uncertain significance	Hypertrophic cardiomyopathy	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 545 of the MYBPC3 protein (p.Leu545Met). This variant is present in population databases (rs377163678, gnomAD 0.05%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027). ClinVar contains an entry for this variant (Variation ID: 164105). 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.
PreventionGenetics, part of Exact Sciences	RCV003422041	SCV004117172	uncertain significance	MYBPC3-related condition	2023-05-26	criteria provided, single submitter	clinical testing	The MYBPC3 c.1633C>A variant is predicted to result in the amino acid substitution p.Leu545Met. This variant was reported in both affected and control individuals in a hypertrophic cardiomyopathy cohort and was considered a polymorphism (Van Driest et al. 2004. PubMed ID: 15519027; Kobayashi et al. 2017. PubMed ID: 28166811). This variant is reported in 0.050% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47363699-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Color Diagnostics, LLC DBA Color Health	RCV003531975	SCV004358717	uncertain significance	Cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 545 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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, but was also present in healthy controls (PMID: 15519027). This variant has been identified in 12/280166 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.