Submissions for variant NM_000256.3(MYBPC3):c.49C>T (p.Arg17Trp)

gnomAD frequency: 0.00002  dbSNP: rs747857800

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520274	SCV000617217	uncertain significance	not provided	2018-11-20	criteria provided, single submitter	clinical testing	The R17W variant of uncertain significance in the MYBPC3 gene has been reported in 1/3,267 individuals with a clinical diagnosis of HCM undergoing genetic testing at Oxford Medical Genetics Laboratories; however, specific clinical and familial segregation information was not provided (Walsh et al., 2017). R17W was observed in 4/16,908 (0.02%) alleles from individuals of East Asian ancestry in the gnomAD dataset (Lek et al., 2016). The R17W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position where only amino acids with similar properties to arginine are tolerated across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV000845098	SCV001210321	uncertain significance	Hypertrophic cardiomyopathy	2023-05-09	criteria provided, single submitter	clinical testing	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. 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: 449293). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs747857800, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 17 of the MYBPC3 protein (p.Arg17Trp).
Color Diagnostics, LLC DBA Color Health	RCV001176837	SCV001340898	uncertain significance	Cardiomyopathy	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan 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 one individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 7/266252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV002341219	SCV002640479	uncertain significance	Cardiovascular phenotype	2020-12-04	criteria provided, single submitter	clinical testing	The p.R17W variant (also known as c.49C>T), located in coding exon 2 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 49. The arginine at codon 17 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in a hypertrophic cardiomyopathy genetic testing cohort; however, details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GenomeConnect, ClinGen	RCV000845098	SCV000986950	not provided	Hypertrophic cardiomyopathy		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 11/30/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.