ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1790G>A (p.Arg597Gln) (rs727503195)

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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, Partners HealthCare Personalized Medicine RCV000497973 SCV000198884 likely pathogenic Hypertrophic cardiomyopathy 2018-06-12 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000505707 SCV000208050 likely pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing The c.1790 G>A (R597Q) likely pathogenic variant has been identified in the MYBPC3 gene. This variant has previously been reported in multiple unrelated individuals diagnosed with HCM (Kimura et al., 2000; Curila et al., 2012; Chiou et al., 2014; Millat et al., 2015). In addition, the c.1790 G>A (R597Q) variant was also observed in other unrelated individuals referred for HCM genetic testing at GeneDx. However, segregation data is uninformative. Furthermore, the ClinVar database reports conflicting interpretations of pathogenicity by outside clinical laboratories (ClinVar SCV000198884.3, SCV000219730.1; Landrum et al., 2016). Nevertheless, this variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. At the protein level, the c.1790 G>A (R597Q) variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at an amino acid residue that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. At the mRNA level, 2/3 in silico splice prediction programs predict varying degrees of damage to the canonical splice donor site. In addition, functional studies by Millat et al. (2015) suggest that the c.1790 G>A (R597Q) variant results in abnormal splicing and skipping of exon 18. Therefore, this variant is likely pathogenic.
Ambry Genetics RCV000248201 SCV000318810 likely pathogenic Cardiovascular phenotype 2017-12-06 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Last nucleotide of exon;Functionally-validated splicing mutation
Center for Human Genetics,University of Leuven RCV000497973 SCV000579519 pathogenic Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score pathogenic
Invitae RCV000497973 SCV000749869 pathogenic Hypertrophic cardiomyopathy 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 597 of the MYBPC3 protein (p.Arg597Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 18 of the MYBPC3 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to segregate with hypertrophic cardiomyopathy (HCM) in a single family (PMID: 25086479) and has been reported in several individuals affected with HCM (PMID: 24111713, 27532257, 27600940,23674513). ClinVar contains an entry for this variant (Variation ID: 164098). Experimental studies have shown that this missense change results in aberrant splicing of exon 18, resulting in an out-of-frame transcript (PMID: 25849606, 28679633). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170951 SCV001333605 uncertain significance Cardiomyopathy 2019-01-15 criteria provided, single submitter clinical testing

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