ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1123G>A (p.Val375Met)

gnomAD frequency: 0.00002  dbSNP: rs727503208
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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 RCV000151143 SCV000198929 uncertain significance not specified 2014-08-18 criteria provided, single submitter clinical testing The Val375Met variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, the clinical significance of the Val375Met variant is uncertain.
Invitae RCV001215230 SCV001386962 uncertain significance Hypertrophic cardiomyopathy 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 375 of the MYBPC3 protein (p.Val375Met). This variant is present in population databases (rs727503208, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 31983221). ClinVar contains an entry for this variant (Variation ID: 164128). 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.
GeneDx RCV001836739 SCV002097450 uncertain significance not provided 2022-02-01 criteria provided, single submitter clinical testing Identified among cohorts of patients with HCM and DCM (Lopes et al., 2015; Walsh et al., 2017; Mazzarotto et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 27532257, 28679633, 31983221)
Ambry Genetics RCV002433651 SCV002751242 uncertain significance Cardiovascular phenotype 2022-08-04 criteria provided, single submitter clinical testing The p.V375M variant (also known as c.1123G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1123. The valine at codon 375 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopahty (DCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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.
Fulgent Genetics, Fulgent Genetics RCV002478426 SCV002790023 uncertain significance Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2021-10-13 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003486669 SCV004239334 uncertain significance Cardiomyopathy 2022-10-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV003486669 SCV004358742 uncertain significance Cardiomyopathy 2023-02-07 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 375 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 at least 3 individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257) and in an individual affected with dilated cardiomyopathy (PMID: 27532257, 31983221). This variant has been identified in 5/278004 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.

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