ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3065G>A (p.Arg1022His) (rs397516000)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201897 SCV000256643 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-03-11 criteria provided, single submitter research The MYBPC3 Arg1022His is a rare variant and is present in the 1000 genomes project (MAF=0.0002; http://www.1000genomes.org/), and absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We identified this variant in 1 HCM proband of Indian descent, who was heterozygous for MYBPC3 Arg1022His, and also carries another variant (LDB3 Gln97Arg) of "uncertain significance". The proband has no family history of disease or SCD. Interestingly, different rare variants at this position (Arg1022Cys, Arg1022Pro, Arg1022Ser) have also been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect, but no prediction is called by PolyPhen-HCM. In summary, based on rarity in the general population and our limited familial data, we have classified MYBPC3 Arg1022His as a variant of "uncertain significance". Further evidence is required to fully understand its pathogenic role in HCM.
Invitae RCV000816293 SCV000956794 uncertain significance Hypertrophic cardiomyopathy 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1022 of the MYBPC3 protein (p.Arg1022His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 28790153, 27532257). ClinVar contains an entry for this variant (Variation ID: 42681). 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. Variants that disrupt the p.Arg1022 amino acid residue in MYBPC3 have been observed in affected individuals (PMID: 16335287, 23396983, 20433692, 24093860). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035554 SCV000059204 uncertain significance not specified 2012-01-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg1022His variant has not been reported in the literature. Arginine (Arg) at position 102 2 is highly conserved in evolutionary distant species, supporting a pathogenic r ole. Our laboratory has detected this variant in one individual of Iraqi descent . This individual was homozygous and severely affected and did not report a fam ily history of HCM, suggesting that the Arg1022His variant has a milder effect i n the heterozygous state. This lab has sequenced the MYBPC3 gene in only a small number of non-Caucasian individuals. In addition, healthy control information i s unavailable so that the full spectrum of benign variation has not yet been def ined for this population. In summary, additional data (control and segregation s tudies) is needed to determine the clinical significance of the Arg1022His varia nt.

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