ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3682C>T (p.Arg1228Cys) (rs201312636)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172557 SCV000054760 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154424 SCV000204092 uncertain significance not specified 2016-05-18 criteria provided, single submitter clinical testing The p.Arg1228Cys variant in MYBPC3 has been identified in 8/3600 individuals of unspecified clinical phenotype from the Framingham and Jackson Heart Studies (Bi ck 2012). It has also been identified in 0.1% (13/9766) of African chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201312636). Additionally, this variant has been identified by our laboratory i n 7 individuals (4 with DCM; 1 with HCM; 1 with early onset severe left ventricu lar dysfunction/ biventricular dilation and 1 with an unspecified complex cardia c phenotype), though it did not segregate with disease in 1 of 3 affected indivi duals from 1 family. This amino acid is not well conserved in evolution which su ggests a change at this amino acid may be tolerated. Collectively, these data su pport that the p.Arg1228Cys variant is less likely disease-causing, though addit ional studies are needed to fully assess its clinical significance.
GeneDx RCV000154424 SCV000208187 uncertain significance not specified 2017-08-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. The R1228C variant has been previously reported in multiple individuals in association with cardiomyopathy (Lakdawala et al., 2012; Paterick et al., 2014; Pugh et al., 2014; Lopes et al., 2015). Lakdawala et al. (2012) reported R1228C in male proband diagnosed with DCM, and his affected mother, but this variant failed to segregate with DCM in his affected sister. Of note, this individual's father was diagnosed with HCM and did not have the R1228C variant (Lakdawala et al., 2012). The R1228C variant was also identified in a 29 year-old male diagnosed with both HCM and LVNC, who also harbored a missense variant in TNNT2, and his mother with LVNC was heterozygous for the MYBPC3 variant only; his father had HCM but did not undergo genetic testing (Paterick et al., 2014). Pugh et al. (2014) also observed R1228C in three individuals with DCM and one individual with severe left ventricular dysfunction and biventricular dilation, while Lopes et al. (2015) reported this variant in another individual with HCM; however, two of these five individuals harbored additional cardiogenetic variants and no segregation data was reported for any of these cases. R1228C is classified as a variant of uncertain significance in ClinVar by at least three other clinical laboratories (ClinVar SCV000204092.3, SCV000219827.2, SCV000318095.1; Landrum et al., 2016), and has been observed both independently, and in conjunction with additional cardiogenetic variants, in multiple individuals referred for cardiomyopathy genetic testing at GeneDx. Thus far, R1228C did not segregate with cardiomyopathy in one affected relative in one family, however, additional informative segregation data is not available for the remaining cases at GeneDx. The R1228C variant was observed at a frequency of approximately 0.13-0.15% of alleles from individuals of African ancestry in the 1000 Genomes Project, the NHLBI Exome Sequencing Project and the Exome Aggregation Consortium. Additionally, the R1228C variant was reported in eight individuals without cardiomyopathy from the Framingham and Jackson Heart Study cohorts, with left ventricular wall thicknesses ranging from 0.78-1.2 cm (Bick et al., 2012). Furthermore, although a follow-up cardiac exam was not reported, R1228C was found in one individual from a cohort of individuals who underwent exome sequencing but were not selected for a history of cardiomyopathy, arrhythmia, or family history of sudden cardiac death (Ng et al., 2013). Nevertheless, R1228C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics RCV000252868 SCV000318095 uncertain significance Cardiovascular phenotype 2017-06-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000172557 SCV000623603 likely benign not provided 2019-02-05 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625350 SCV000745025 uncertain significance Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000172557 SCV000842847 uncertain significance not provided 2018-03-23 criteria provided, single submitter clinical testing
Color RCV000771800 SCV000904497 uncertain significance Cardiomyopathy 2018-06-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the Ig-like domain C10 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy, who also carried a pathogenic variant in the same gene (PMID: 29121657). This variant has been identified in 32/24010 African chromosomes (0.13%) in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
Mendelics RCV000625350 SCV001138285 benign Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148670 SCV000190394 uncertain significance Primary dilated cardiomyopathy 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000154424 SCV000280266 uncertain significance not specified 2015-04-08 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. MYBPC3 p.Arg1228Cys Given the weak case data, failure to segregate, and presence in general population samples, we consider this a variant of uncertain significance. This variant has not been reported in published literature. In a publication on the Laboratory for Molecular Medicine’s (LMM) experience with sequencing for DCM, this variant is noted in a table of variants for which genotyping probes were added to the chip (Zimmerman et al 2010). The Seidmans reported on the occurrence of this variant in the Jackson Heart Study (Bick et al 2012). They found that individuals with multiple rare MYBPC3 variants (including this variant) had a 14-15% lower left ventricular wall thickness. This is a semi-conservative amino acid change with a positively charged Arginine replaced with a neutral Cysteine. This replacement could affect disulfide bonding in the resulting protein. In silico analysis (PolyPhen2) predicts this amino acid change to be probably damaging to the structure/function of the protein. Arginine is highly conserved at this position across species. In total the variant has been seen in ~7 of 6664 laboratory controls and individuals from publicly available population datasets. It is most frequent in African American samples with 0.25% of such individuals carrying the variant. The variant was reported online in 2 of 4137 Caucasian individuals and 5 of 1933 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 7th, 2014). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is listed in dbSNP (rs201312636) with entries for the ESP data and the exome chip designed from the ESP data.

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