Submissions for variant NM_000256.3(MYBPC3):c.3170C>T (p.Thr1057Met)

gnomAD frequency: 0.00002  dbSNP: rs754115924

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000621181	SCV000740103	uncertain significance	Cardiovascular phenotype	2022-07-11	criteria provided, single submitter	clinical testing	The p.T1057M variant (also known as c.3170C>T), located in coding exon 29 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3170. The threonine at codon 1057 is replaced by methionine, an amino acid with similar properties. This alteration has been reported once in a hypertrophic cardiomyopathy (HCM) cohort (Millat G et al. Clin. Chim. Acta, 2010 Dec;411:1983-91). 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	RCV000817663	SCV000958240	uncertain significance	Hypertrophic cardiomyopathy	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1057 of the MYBPC3 protein (p.Thr1057Met). This variant is present in population databases (rs754115924, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20800588). ClinVar contains an entry for this variant (Variation ID: 520333). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	RCV001180596	SCV001345555	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1057 of the MYBPC3 protein. Computational prediction tool indicates that this variant may have a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 4/271254 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.
GeneDx	RCV001546438	SCV001765955	uncertain significance	not provided	2022-09-23	criteria provided, single submitter	clinical testing	Identified in a patient with HCM in published literature (Millat et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20800588)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001180596	SCV002042193	uncertain significance	Cardiomyopathy	2020-07-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483737	SCV002784481	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-09-02	criteria provided, single submitter	clinical testing