ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2458C>T (p.Arg820Trp) (rs775404728)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000604898 SCV000733040 likely pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000176522 SCV000228192 uncertain significance not provided 2015-05-04 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000604898 SCV000743553 pathogenic Familial hypertrophic cardiomyopathy 4 2014-10-08 criteria provided, single submitter clinical testing
Invitae RCV000458652 SCV000546424 likely pathogenic Hypertrophic cardiomyopathy 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 820 of the MYBPC3 protein (p.Arg820Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs775404728, ExAC 0.009%). This variant has been reported in the heterozygous state in individuals affected with hypertrophic cardiomyopathy (PMID: 28771489, Invitae). It has also been reported in the homozygous state in two related individuals affected with hypertrophic cardiomyopathy and left ventricular non-compaction; however, heterozygous carriers in this family were unaffected (PMID: 20542340). ClinVar contains an entry for this variant (Variation ID: 195850). Experimental studies have shown that felines with an equivalent variant develop hypertrophic cardiomyopathy (PMID: 17521870), however the clinical significance of this observation is uncertain. A different missense substitution at this codon (p.Arg820Gln) has been determined to be pathogenic (PMID: 12628722, 22112859, 22267749). This suggests that the arginine residue is critical for MYBPC3 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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