ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3613C>T (p.Arg1205Trp) (rs727503171)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151066 SCV000198805 uncertain significance not specified 2014-11-10 criteria provided, single submitter clinical testing The p.Arg1205Trp variant in MYBPC3 has been reported in 1 individual with HCM (B os 2014) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, the clinical significance of the p.Arg1205Trp variant is uncertain.
GeneDx RCV000151066 SCV000208181 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The R1205W variant of uncertain significance in the MYBPC3 gene has been reported previously in association with HCM; however, no detailed clinical information or segregation data was reported (Bos et al., 2014; Walsh et al., 2017). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1205W variant 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. Additionally, 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.
Blueprint Genetics RCV000208211 SCV000264041 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-10-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000604457 SCV000372282 uncertain significance Familial hypertrophic cardiomyopathy 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000377792 SCV000372284 uncertain significance Left ventricular noncompaction 10 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000604457 SCV000745026 uncertain significance Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000263553 SCV000828899 uncertain significance Hypertrophic cardiomyopathy 2019-06-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1205 of the MYBPC3 protein (p.Arg1205Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs727503171, ExAC 0.02%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 24793961, 27532257, 30206291). ClinVar contains an entry for this variant (Variation ID: 164032). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171124 SCV001333804 uncertain significance Cardiomyopathy 2018-03-15 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000604457 SCV000733026 uncertain significance Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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