Submissions for variant NM_000256.3(MYBPC3):c.1664T>C (p.Met555Thr)

gnomAD frequency: 0.00001  dbSNP: rs730880692

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158434	SCV000208369	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing	This missense change is denoted p.Met555Thr (M555T) at the protein level and c.1664 T>C at the cDNA level. The Met555Thr variant in the MYBPC3 gene has been reported previously in one individual with HCM and one individual with DCM (Girolami, 2006; Hershberger, 2010). Considering all publications, the Met555Thr variant was absent from 692 control individuals of various ethnic backgrounds, however Hershberger et al. (2010) described the Met555Thr variant as possibly disease-causing" due to the lack of affected relatives to evaluate whether Met555Thr co-segregated with a DCM phenotype (Girolami, 2006; Hershberger, 2010). The Met555Thr was also not detected in up to 200 alleles from control individuals of Caucasian ancestry, indicating it is not a common benign variant in this population. While Met555Thr results in a non-conservative amino acid substitution of a non-polar Methionine with a neutral, polar Threonine, the Met555 residue is not conserved across species, with several mammal species normally harboring a Threonine at this residue. In addition, the Met555Thr is located in a region of the MYBPC3 gene with few missense mutations, suggesting this region of the protein may tolerate change. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine whether the Met555Thr variant is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s)."
Invitae	RCV001035559	SCV001198888	uncertain significance	Hypertrophic cardiomyopathy	2022-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 555 of the MYBPC3 protein (p.Met555Thr). This variant is present in population databases (rs730880692, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 16858239, 20215591, 26656175). ClinVar contains an entry for this variant (Variation ID: 181121). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001180562	SCV001345520	likely benign	Cardiomyopathy	2019-11-08	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196344	SCV001366945	uncertain significance	Hypertrophic cardiomyopathy 4	2019-10-03	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4.
Baylor Genetics	RCV001196344	SCV001520468	uncertain significance	Hypertrophic cardiomyopathy 4	2020-04-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002390380	SCV002703325	likely benign	Cardiovascular phenotype	2021-07-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.