Submissions for variant NM_000071.3(CBS):c.434C>T (p.Pro145Leu)

dbSNP: rs121964963

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625555	SCV000930439	likely pathogenic	Classic homocystinuria	2019-04-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002227955	SCV001393783	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 145 of the CBS protein (p.Pro145Leu). This variant is present in population databases (rs121964963, gnomAD 0.006%). This missense change has been observed in individual(s) with homocystinuria (PMID: 8353501, 16479318, 24211323, 25218699). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 118). 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%. Experimental studies have shown that this missense change affects CBS function (PMID: 8353501, 22267502). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV001250193	SCV001424384	likely pathogenic	Homocystinuria		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000625555	SCV004215561	pathogenic	Classic homocystinuria	2024-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001250193	SCV005381641	pathogenic	Homocystinuria	2024-08-01	criteria provided, single submitter	clinical testing	Variant summary: CBS c.434C>T (p.Pro145Leu) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249936 control chromosomes. c.434C>T has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Homocystinuria (Kozich_1993, Urreizti_2006, Karaca_2014, Alcaide_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in residual enzymatic activity and nonfunctional yeast cells in yeat growth assays (Mayfield_2012). The following publications have been ascertained in the context of this evaluation (PMID: 25218699, 24211323, 8353501, 22267502, 16479318). ClinVar contains an entry for this variant (Variation ID: 118). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000000139	SCV000020282	pathogenic	Homocystinuria, pyridoxine-responsive	1993-06-01	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000625555	SCV000746051	pathogenic	Classic homocystinuria	2017-09-18	no assertion criteria provided	clinical testing