21-43062358-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000071.3(CBS):c.992C>A(p.Ala331Glu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A331V) has been classified as Pathogenic.
Frequency
Consequence
NM_000071.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 0
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250866Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135762
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 2712Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 1428
GnomAD4 genome Cov.: 0
ClinVar
Submissions by phenotype
Classic homocystinuria Pathogenic:1
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not provided Pathogenic:1
Reported in a patient with homocystinuria who also harbors a frameshift variant in the CBS gene (Dawson et al., 1997; Gaustadnes et al., 2002); Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 212857; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Published functional studies demonstrate a damaging effect on protein function (Mayfield et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12124992, 12686134, 22267502, 9156316, 31301157) -
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 331 of the CBS protein (p.Ala331Glu). This variant is present in population databases (rs777919630, gnomAD 0.0009%). This missense change has been observed in individual(s) with homocystinuria (PMID: 9156316; Invitae). ClinVar contains an entry for this variant (Variation ID: 212857). 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: 9156316, 22267502). For these reasons, this variant has been classified as Pathogenic. -
Homocystinuria Pathogenic:1
Variant summary: CBS c.992C>A (p.Ala331Glu) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain 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 250866 control chromosomes. c.992C>A has been reported in the literature in one individual affected with Homocystinuria in the compound heterozygous state (Dawson_1996, Gaustadnes_2002). Additionally, the variant has been reported to reduce CBS activity to less than 1% of wild-type, and was shown to be non-functional in a yeast-based assay (Dawson_1996, Mayfield_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at