ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2003G>A (p.Arg668His) (rs727503191)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201899 SCV000256640 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-07-21 criteria provided, single submitter research This MYBPC3 Arg668His has been previously identified in multiple unrelated HCM cases (Morner S. et al., 2003; Song L. et al., 2005; Alfares AA. et al., 2015). Familial segregation in one HCM family by Wang H. et al., (2008) found 3 HCM affecteds and 1 clinically unaffected to carry this variant. Similarly, familial investigation by Morner S. et al., (2003) identified clinically unaffected individuals to carry this MYBPC3 Arg668His variant. We have identified the MYBPC3 Arg668His variant in an HCM proband where two additional variants in MYBPC3 and MYH7 have also been observed in the family (Girolami F, et al., 2010). One of the additional variants (MYBPC3 Gln969*) is well described as disease-causing. Segregation analysis showed this MYBPC3 Arg668His variant to be present in one other clinically unaffected family member who carried an additional MYH7 Arg1079Gln variant (VUS). This variant is not observed in the 1000 genomes project (http://www.1000genomes.org/), but occurs in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.0002696. Furthermore, the MYBPC3 Arg668His has been identified in isolation in a heart study population (Bick AG, et al., 2012) and an HCM cohort (Alfares AA et al., 2015), but there is no further evidence provided in these studies to support a pathogenic role. Arginine (Arg) at position 668 is highly conserved across distantly related species and in silico tools SIFT and MutationTaster predict the impact of this variant to be "deleterious" and "disease-causing", respectively. No prediction is made by PolyPhen-HCM. Due to the possibility of incomplete disease penetrance in our family, limited segregation analysis due to small number of informative individuals, and co-occurrence with a MYBPC3 variant (Gln969*) that explains the disease phenotype, we classify this MYBPC3 Arg668His variant as one of "uncertain significance".
Blueprint Genetics RCV000151106 SCV000264032 likely benign not specified 2015-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000766737 SCV000617253 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing The R668H variant of uncertain significance in the MYBPC3 gene has been reported previously in association with HCM (Morner et al., 2003; Song et al., 2005; Girolami et al., 2010). Initially, Morner et al., 2003 reported the R668H variant in two unrelated individuals with HCM, and was absent from 200 control alleles. Subsequently, this variant has been reported in at least one Chinese individual with HCM, and in one individual with HCM who also harbored additional variants in the MYH7 and MYBPC3 genes (Song et al., 2005; Girolami et al., 2010). Cann et al., 2016 reported this variant in one individual with HCM suspected on autopsy and in 27 relatives, three of which were reported to be clinically affected; detailed diagnostic criteria was not provided. This variant has also been reported in two unrelated individuals tested for cardiomyopathy at GeneDx. Additionally, the R668H variant was observed in 31/65808 alleles (~0.05%) from individuals of European (non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC).Although the R668H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Ambry Genetics RCV000621094 SCV000740000 uncertain significance Cardiovascular phenotype 2016-08-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000628998 SCV000749908 uncertain significance Hypertrophic cardiomyopathy 2017-09-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 668 of the MYBPC3 protein (p.Arg668His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs727503191, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy. However, in some of these individuals it has been found in combination with a pathogenic variant in MYBPC3 (p.Gln969*) (PMID: 12818575, 15563892, 20359594, 25335496, 28790153). ClinVar contains an entry for this variant (Variation ID: 164090). 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.
Mendelics RCV000988543 SCV001138300 benign Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151106 SCV000198869 uncertain significance not specified 2013-02-11 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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