ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2450G>A (p.Arg817Gln) (rs397515964)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766352 SCV000208093 uncertain significance not provided 2013-08-14 criteria provided, single submitter clinical testing p.Arg817Gln (CGG>CAG): c.2450 G>A in exon 25 of the MYBPC3 gene (NM_000256.3). The Arg817Gln variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, however this variant has been observed in multiple unrelated individuals tested for HCM. Arg817Gln results in non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a position that is conserved across mammalian species. The NHLBI Exome Sequencing Project reports Arg817Gln was not observed in approximately 6,500 individuals of European and African American ancestry, indicating it is not a common benign variant in these populations. However, variants in nearby residues (Arg820Gln, Ala833Thr, Ala833Val) have been reported healthy individuals of various ethnic backgrounds, indicating this region of the protein may tolerate change (dbSNP). With the clinical and molecular information available at this time, we cannot definitively determine if Arg817Gln is a disease-causing mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae RCV000459809 SCV000546496 likely pathogenic Hypertrophic cardiomyopathy 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 817 of the MYBPC3 protein (p.Arg817Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs397515964, ExAC 0.01%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42621). 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. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035489 SCV000059139 uncertain significance not specified 2011-02-24 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg817Gln v ariant has not been reported in the literature. This variant has been identified by our laboratory in 2 other HCM probands (1 Asian, 1 Black). The variant was not detected in 414 White and 368 Black control chromosomes, suggesting this var iant is not common in these populations. Furthermore, arginine (Arg) at position 817 is highly conserved across several species, indicating the change observed in this individual may negatively affect the MYBPC3 protein function. In summary , absence from healthy controls and evolutionary conservation of the amino acid are consistent with a pathogenic role; however, additional studies are needed to determine its significance with certainty.

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