Submissions for variant NM_000071.3(CBS):c.340G>A (p.Ala114Thr)

dbSNP: rs377708532

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493781	SCV000582275	likely pathogenic	not provided	2015-09-02	criteria provided, single submitter	clinical testing	The A114T variant has not been published as a pathogenic variant or been reported as a benign polymorphism to our knowledge. The A114T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A114T 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. In addition, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in the same residue (A114V) and missense variants in nearby residues (C109R, G116R, R121C, R121H, R121L) have been reported in the Human Gene Mutation Database in association with homocystinuria (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae	RCV002231627	SCV001544434	likely pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the CBS protein (p.Ala114Thr). This variant is present in population databases (rs377708532, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 429655). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. This variant disrupts the p.Ala114 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7762555, 8353501, 20490928, 20506325, 22069143, 22267502, 22612060). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.