ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2684G>A (p.Arg895His)

gnomAD frequency: 0.00019  dbSNP: rs372628478
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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, Mass General Brigham Personalized Medicine RCV000035520 SCV000059170 uncertain significance not specified 2011-05-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg895His v ariant has not been reported in the literature. It has been previously detected in 1/>2,700 probands unknown racial background tested by our laboratory. Arginin e (Arg) at amino acid position 895 is highly conserved across evolutionarily dis tant species, increasing the likelihood that the change is pathogenic. In additi on, two computer tools (PolyPhen2 and SIFT) predict this change to be deleteriou s; however, their accuracy has not been clinically validated. It should be noted that this laboratory has sequenced the MYBPC3 gene in only a limited number of non-Caucasian individuals to date and can therefore not exclude that the Arg895H is variant is common on other populations. In summary, the data available so far is consistent with a pathogenic role but additional data (healthy control and f amilial segregation studies) is needed to determine this with certainty.
GeneDx RCV000766360 SCV000208117 uncertain significance not provided 2022-12-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 25132132)
Invitae RCV000690258 SCV000817939 uncertain significance Hypertrophic cardiomyopathy 2024-01-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 895 of the MYBPC3 protein (p.Arg895His). This variant is present in population databases (rs372628478, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25132132). ClinVar contains an entry for this variant (Variation ID: 42651). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Mendelics RCV000988539 SCV001138294 uncertain significance Hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001188364 SCV001355413 uncertain significance Cardiomyopathy 2023-03-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 895 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25132132) and in an individual affected with dilated cardiomyopathy (PMID: 35284542). This variant has been identified in 16/208502 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001188364 SCV003838269 uncertain significance Cardiomyopathy 2022-04-19 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000766360 SCV002034259 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000766360 SCV002034408 uncertain significance not provided no assertion criteria provided clinical testing

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