ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.713G>A (p.Arg238His) (rs727504396)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154567 SCV000204240 uncertain significance not specified 2018-04-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg238His var iant in MYBPC3 has been reported in 1 individual with DCM (Waldmuller 2011). Thi s variant has been identified by our laboratory in 1 Asian adult with HCM who ca rried another pathogenic MYBPC3 variant and 1 Caucasian family with several memb ers having various cardiomyopathy presentations including LVNC, mild LVH and sev ere, neonatal DCM. In this family, two infants with neonatal DCM had the Arg238H is variant in addition to a variant in ACTC1. The ACTC1 variant was present in three paternal relatives who had either mild LVH or LVNC and is suspected to be disease causing. The MYBPC3 Arg238His variant was inherited from the unaffected mother. Computational prediction tools and conservation analysis suggest that t he p.Arg238His variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. However, this variant has been ident ified in 0.05% (17/33486) of Latino chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504396). This variant h as been reported in ClinVar (Variant ID:177910). In summary, the clinical signif icance of the p.Arg238His variant is uncertain and its frequency suggests that i t is less likely to be disease causing on its own. ACMG/AMP Criteria applied: PP 3; BS1.
GeneDx RCV000766313 SCV000208243 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. The R238H variant has been published in association with both DCM and HCM (Waldmuller et al., 2011; Pugh et al., 2014; Walsh et al, 2017). Specific clinical and segregation data were not provided in these reports, and at least one individual harbored co-occurring cardiogenetic variants (Pugh et al., 2014). This variant has also been identified in several unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, though clinical details are limited and some individuals harbored additional cardiogenetic variants. No internal segregation data are available. The R238H variant is observed in 17/33,486 (0.05%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, R238H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000198900 SCV000254439 uncertain significance Hypertrophic cardiomyopathy 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 238 of the MYBPC3 protein (p.Arg238His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs727504396, ExAC 0.05%). This variant has been observed in several individuals affected with dilated or hypertrophic cardiomyopathy (PMID: 21750094, 27532257). ClinVar contains an entry for this variant (Variation ID: 177910). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000615468 SCV000743572 uncertain significance Familial hypertrophic cardiomyopathy 4 2017-08-17 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000615468 SCV000744868 uncertain significance Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Color RCV000771899 SCV000904663 uncertain significance Cardiomyopathy 2018-10-15 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the Ig-like domain C1 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has also been identified in 26/244896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000154567 SCV000280279 uncertain significance not specified 2015-03-30 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.Arg238His Based on the data reviewed below, we consider this a variant of unknown significance (VUS). This variant has been reported previously in 2 unrelated cases of DCM, with difficult-to-interpret segregation data available from one family (Waldmiller et al. 2011, Supplementary Data; Pugh et al. 2014-Supplementary Data from Laboratory for Molecular Medicine). Waldmiller et al. found it in a Caucasian patient with DCM recruited in Germany. The Laboratory for Molecular Medicine found it in a Caucasian patient with DCM and biventricular dysfunction with fetal onset who also had several other variants in genes associated with cardiomyopathy (identified on a 46-gene pan-cardiomyopathy panel). Other variants in ACTC1 and NEXN carried by the same patient were classified as “VUS-favor pathogenic”; there were also VUSs found in TTN and PKP2. The LMM has also found this variant in an Asian proband with HCM who carried a second, pathogenic variant. LMM classifies p.Arg238His in MYBPC3 as a VUS (with no weighting in either direction, toward “likely” or “not likely” disease-causing). This is a conservative amino acid change from a positively-charged arginine to a positively-charged histidine, although the side-chains are very different in shape. The arginine at codon 238 is highly conserved (100% across 9 vertebrate species) as are the amino acids on either side. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Missense variants at nearby residues have been listed in HGMD in association with cardiomyopathy, supporting the functional importance of this region of the protein. In particular, 3 different amino acid variants at the adjacent codon 237 have been seen in association with cardiomyopathy: Asp228Asn, Ser236Gly, Tyr237Cys, Tyr237His, Tyr237Ser, Glu240Asp, Ser242Pro (HGMD professional version as of January 17, 2014). In total the variant has not been seen in ~6200 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. The phenotype of the ESP 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. There is no variant at codon 238 listed in dbSNP or 1000 genomes (as of March 18, 2014).
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000615468 SCV000733062 uncertain significance Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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