Submissions for variant NM_000256.3(MYBPC3):c.50G>A (p.Arg17Gln)

gnomAD frequency: 0.00010  dbSNP: rs374630007

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151174	SCV000198992	uncertain significance	not specified	2013-05-01	criteria provided, single submitter	clinical testing	The Arg17Gln variant in MYBPC3 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8408 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The affected amino acid is not well conserved in evolution, suggesting that a change may be tolerated. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. At this time, additional information is needed to fully asses s the clinical significance of this variant.
GeneDx	RCV000766303	SCV000208113	uncertain significance	not provided	2018-03-07	criteria provided, single submitter	clinical testing	The R17Q variant of uncertain significance in the MYBPC3 gene has previously been reported in one patient with HCM with no family history of the disease, but was also present in 1/200 healthy control individuals (Garcia-Castro et al., 2008). This variant has been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiac genetic testing at GeneDx; however, thus far, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. This variant is observed in 9/32876 (0.03%) alleles from individuals of Latino ancestry and in 9/105042 (0.01%) alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the R17Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.
Ambry Genetics	RCV000619032	SCV000740010	uncertain significance	Cardiovascular phenotype	2022-01-12	criteria provided, single submitter	clinical testing	The p.R17Q variant (also known as c.50G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 50. The arginine at codon 17 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM); however, clinical details were limited and additional alterations in other cardiac-related genes were identified in some cases (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000701754	SCV000830569	uncertain significance	Hypertrophic cardiomyopathy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 17 of the MYBPC3 protein (p.Arg17Gln). This variant is present in population databases (rs374630007, gnomAD 0.03%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25342278, 29121657, 30871747; Invitae). ClinVar contains an entry for this variant (Variation ID: 164160). 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. 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	RCV000777988	SCV000914094	uncertain significance	Cardiomyopathy	2023-10-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 17 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 25342278, 28356264, 28771489, 29121657, 30442288, 34555931), in one individual with dilated cardiomyopathy (PMID: 30871747), and in two related individuals who were reported to be normal (PMID: 34555931). One of the affected probands also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 34555931). This variant has also been identified in 20/235814 chromosomes (10/33652 Latino chromosomes, 0.0297%) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals and has also been observed at an elevated allele frequency in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000766303	SCV001714975	uncertain significance	not provided	2020-07-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777988	SCV002042220	uncertain significance	Cardiomyopathy	2021-08-17	criteria provided, single submitter	clinical testing