ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.961G>A (p.Val321Met) (rs200119454)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151148 SCV000198937 uncertain significance not specified 2016-08-04 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val321Met var iant in MYBPC3 has been identified in 2 individuals with DCM, 6 individuals with HCM, 1 individual with LVNC and 1 individual with TOF (Hoedemaekers 2011, Waldm uller 2011, Maron 2012, Lopes 2013, Miller 2013, LaHaye 2016, LMM unpublished da ta). It has also been identified in 0.1% (36/45024) of European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2 00119454). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, while the clinical significance of the p.Val321Met variant is uncertain, its frequency and the broad spectrum of a ssociated diseases suggest that it is more likely to be benign.
GeneDx RCV000487620 SCV000208258 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing The V321M variant of uncertain significance in the MYBPC3 has previously been reported in association with DCM and HCM (Waldmuller et al., 2011; Maron et al., 2012; Lopes et al., 2013; Miller et al., 2013; Lopes et al., 2015). However, some reported individuals also harbored variants in other cardiomyopathy-related genes. The V321M variant has also been observed, both independently and in conjunction with additional cardiogenetic variants, in multiple other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data are limited or absent for these individuals. Furthermore, the V321M is observed in 67/121316 (0.05%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The V321M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000487620 SCV000261724 likely benign not provided 2018-10-25 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000148683 SCV000264023 uncertain significance Primary dilated cardiomyopathy 2015-02-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000242053 SCV000319673 uncertain significance Cardiovascular phenotype 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487620 SCV000574882 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627153 SCV000747984 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-09-06 criteria provided, single submitter clinical testing
Color RCV000771880 SCV000904637 uncertain significance Cardiomyopathy 2018-10-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the MyBP-C motif of the myosin (S2) binding region of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23396983, 23054336) and dilated cardiomyopathy (PMID: 21750094, 27930701). This variant has also been identified in 87/266806 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000771880 SCV000995126 uncertain significance Cardiomyopathy 2017-09-08 criteria provided, single submitter clinical testing
Mendelics RCV000988549 SCV001138312 uncertain significance Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148683 SCV000190408 uncertain significance Primary dilated cardiomyopathy 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000151148 SCV000280289 uncertain significance not specified 2015-06-23 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val321Met (c.961G>A) in the MYBPC3 gene. Data on the variant is reviewed below. Given that many of the patients with this variant have an additional variant and also that p.Val321Met is present in a general population sample, we consider it a variant of uncertain significance. In total, the variant has been seen in 6 cases of cardiomyopathy (not including the patient) with no segregation data available. Notably, in 3 of 6 cases the patients carried at least one other rare sarcomere variant (and in 2 of 6 cases data is not available on the presence or absence of additional variants). Waldmuller et al (2011) observed the variant in one individual with DCM out of 888 individuals with HCM or DCM studied (note that this allele frequency is consistent with the allele frequency observed in the NHBLI dataset). They sequenced MYBPC3 and MYH7 in this cohort and did note that some patients had multiple variants however they don't specify which variants were seen in the presence of another variant. The variant was also observed in one of 327 Dutch individuals with HCM and was classified as a variant of uncertain significance in that study (Hoedemakers et al in http://repub.eur.nl/res/pub/22183/110114_Michels,%20Michelle.pdf). They only report on analysis of MYBPC3. It has also been seen by GeneDx in two other patients with HCM. One of them also had another variant in MYBPC3, which GeneDx described as a "published mutation" (the did not share what the variant was). McKenna's group observed the variant in one out of 223 HCM probands in their UK cohort (Lopes et al 2013). That patient also carried p.Lys351Glu in MYH7 and p.Val176Met in TNNI3 (we have not reviewed either of these variants). Maron et al (2012) reported the variant in a patient with HCM who also carried p.Val411IIe in MYH7 (we have not reviewed that variant). The reported cohort of 330 patients was drawn from the Tufts, Minneapolis heart institute, and Sydney HCM centers. The variant is not currently listed in ClinVar (as of November 20th, 2014). This is a conservative amino acid substitution with a nonpolar Valine replaced with a nonpolar Methionine. The amino acid change is located in a highly conserved domain of the protein and residue 321 is conserved across mammals, however it is an Alanine in Elegans. In silico analysis with Polyphen 2 predicts the variant to be probably damaging. Additional variants in nearby codons (p.Ser311Leu, p.Arg326Gln) have been reported in association with cardiomyopathy. In total the variant is present in 5 of 6408 individuals from publicly available databases. The variant was reported in the NHLBI Exome Sequencing Project data set in 4 of 4250 Caucasian individuals and 1 of 2158African-American individuals (as of December 28, 2011). The phenotype of these individuals is not publicly available, however the cohort has been screened to exclude individuals with evidence of Mendelian cardiac disease. GeneDx reports that the variant was absent in 353 presumably healthy individuals of mixed ancestry. The variant is listed in dbSNP (rs200119454); the ESP data is the only data referenced in the dbSNP entry. I also checked the Exome Aggregation Consortium dataset, a newly released dataset of exomes on ~64,000 individuals from a variety of research studies. This overlaps with the ESP data reviewed above. We are still reviewing this dataset and assessing how to apply it clinically. The datasets includes 37 heterozygotes with this variant, out of a total of 40,521 individuals of varied ancestries. The highest frequency is 36 heterozygotes in 22,820 individuals of European decent. Phenotype is available on one of those patients, published by the Seidman group, in a paper on rare sarcomere variants in Jackson Heart and Framingham. That individual had a left ventricular wall thickness of 1.18 cm.

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