ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2560A>G (p.Met854Val)

gnomAD frequency: 0.00004  dbSNP: rs373171036
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035510 SCV000059160 uncertain significance not specified 2010-01-27 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000623691 SCV000740359 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-09-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000822901 SCV000963724 uncertain significance Hypertrophic cardiomyopathy 2025-01-22 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 854 of the MYBPC3 protein (p.Met854Val). This variant is present in population databases (rs373171036, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 29247119, 37652022). ClinVar contains an entry for this variant (Variation ID: 42642). 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 tolerated. 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.
GeneDx RCV001588843 SCV001826856 uncertain significance not provided 2022-02-22 criteria provided, single submitter clinical testing Reported in association with HCM and sudden unexplained death (Walsh et al., 2017; Lin et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42642; ClinVar); This variant is associated with the following publications: (PMID: 29247119, 27532257)
Ambry Genetics RCV003162301 SCV003911244 uncertain significance Cardiovascular phenotype 2022-12-08 criteria provided, single submitter clinical testing The c.2560A>G (p.M854V) alteration is located in exon 25 (coding exon 25) of the MYBPC3 gene. This alteration results from a A to G substitution at nucleotide position 2560, causing the methionine (M) at amino acid position 854 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV000822901 SCV004839233 uncertain significance Hypertrophic cardiomyopathy 2023-10-06 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 854 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 at least one individual affected with hypertrophic cardiomyopathy (PMID: 27532257) and in one individual who experienced sudden unexplained death (PMID: 29247119). This variant has been identified in 3/276678 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.
Fulgent Genetics, Fulgent Genetics RCV005049402 SCV005684635 uncertain significance Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2024-05-03 criteria provided, single submitter clinical testing

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