Submissions for variant NM_000256.3(MYBPC3):c.3223A>G (p.Thr1075Ala)

gnomAD frequency: 0.00001  dbSNP: rs767927162

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493715	SCV000582665	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The T1075A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1075A 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. However, this substitution occurs at a position that is not conserved across species and alanine (A) is the wild-type residue at this position in multiple mammalian species. In silico analysis predicts this variant likely does not alter the protein structure/function.
Color Diagnostics, LLC DBA Color Health	RCV001188960	SCV001356151	uncertain significance	Cardiomyopathy	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1075 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 not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 7/210346 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.
Invitae	RCV002527095	SCV003242580	uncertain significance	Hypertrophic cardiomyopathy	2023-06-25	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 429967). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This variant is present in population databases (rs767927162, gnomAD 0.02%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1075 of the MYBPC3 protein (p.Thr1075Ala).
Ambry Genetics	RCV003302729	SCV003989424	uncertain significance	Cardiovascular phenotype	2023-03-24	criteria provided, single submitter	clinical testing	The p.T1075A variant (also known as c.3223A>G), located in coding exon 30 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 3223. The threonine at codon 1075 is replaced by alanine, an amino acid with similar properties. This amino acid position is poorly 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000493715	SCV004565020	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	The MYBPC3 c.3223A>G; p.Thr1075Ala variant (rs767927162), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 429967). This variant is found in the Latino/Admixed American population with an allele frequency of 0.023% (7/30528 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.085). Due to limited information, the clinical significance of this variant is uncertain at this time.