ClinVar Miner

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

dbSNP: rs397516000
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Total submissions: 6
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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 RCV000035554 SCV000059204 uncertain significance not specified 2019-08-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1022His variant in MYBPC3 has been identified in 2 individuals with HCM, one of whom was homozygous (Burns 2017, LMM data). It was also identified in 2/278058 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID#42681). Computational tools suggest that this variant may impact protein function; however, this information is not predictive enough to determine pathogenicity. In addition, two other variants involving this codon, p.Arg1022Cys and p.Arg1022Pro, have been identified in individuals with HCM, suggesting that changes at this position may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM5_Supporting, PP3.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000201897 SCV000256643 uncertain significance 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 2023-03-08 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 42681). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 28790153, 33782553; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1022 of the MYBPC3 protein (p.Arg1022His). This variant disrupts the p.Arg1022 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16335287, 20433692, 23396983, 24093860). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health RCV001179299 SCV001343930 uncertain significance Cardiomyopathy 2023-03-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 1022 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 individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28408708, 28790153, 32841044, 33782553). This variant has been identified in 2/278058 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Arg1022Pro and p.Arg1022Cys, have been reported as disease-causing (ClinVar variation ID: 42682 and 42680), suggesting that arginine at this position is important for MYBPC3 protein function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics RCV002223767 SCV002503394 uncertain significance not provided 2020-06-23 criteria provided, single submitter clinical testing
GeneDx RCV002223767 SCV002586896 uncertain significance not provided 2022-10-17 criteria provided, single submitter clinical testing Reported in patients with HCM in the published literature (Walsh et al., 2017; Ingles et al., 2017; Burns et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28408708, 33782553, 27532257, 28790153)

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