Submissions for variant NM_000256.3(MYBPC3):c.1591G>T (p.Gly531Trp)

dbSNP: rs397515912

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV005054287	SCV001156264	uncertain significance	Hypertrophic cardiomyopathy 4	2018-04-04	criteria provided, single submitter	research	MYBPC3 Gly531Trp is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in proband with mild concentric hypertrophy but not diagnostic of HCM. Interestingly another amino acid change at this position (Gly531Arg) has been classified as likely pathogenic. In silico tools SIFT, PolyPhen-2 and MutationTaster predict the variant to be deleterious. In summary, this variant is rare, a different amino acid change has been reported as likely pathogenic at this position and in silico tools predict it to be deleterious therefore we classify MYBPC3 Gly531Trp as a variant of 'uncertain significance'.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000999568	SCV001393903	uncertain significance	Hypertrophic cardiomyopathy	2024-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 531 of the MYBPC3 protein (p.Gly531Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 810736). 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. This variant disrupts the p.Gly531 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 20624503, 21750094, 23508784, 27483260, 27532257, 27600940, 28356264). 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.
Ambry Genetics	RCV002400178	SCV002706796	uncertain significance	Cardiovascular phenotype	2023-06-06	criteria provided, single submitter	clinical testing	The p.G531W variant (also known as c.1591G>T), located in coding exon 17 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 1591. The glycine at codon 531 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486953	SCV004239344	likely pathogenic	Cardiomyopathy	2023-01-09	criteria provided, single submitter	clinical testing