21-43066369-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000071.3(CBS):āc.325T>Cā(p.Cys109Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C109Y) has been classified as Likely 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.325T>C | p.Cys109Arg | missense_variant | 5/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.325T>C | p.Cys109Arg | missense_variant | 5/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 1AN: 53796Hom.: 0 Cov.: 7 FAILED QC
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250848Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135692
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000856 AC: 59AN: 689364Hom.: 3 Cov.: 9 AF XY: 0.0000778 AC XY: 28AN XY: 359768
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000186 AC: 1AN: 53796Hom.: 0 Cov.: 7 AF XY: 0.0000394 AC XY: 1AN XY: 25350
ClinVar
Submissions by phenotype
Classic homocystinuria Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 12, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2019 | The p.Cys109Arg variant in CBS has been reported in the compound heterozygous state in 3 individuals and in the heterozygous state in 1 individual with homocystinuria (Gaustadnes 2002, Voskoboeva 2018). It has also been identified in 3/113348 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In vitro functional studies support an impact on protein function (Mayfield 2012), though these studies may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PM3_Strong, PM2, PS3_Moderate. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 17, 2018 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2022 | In a yeast system lacking the CBS ortholog, expression of a construct with C109R showed a failure to restore function/rescue growth (Gaustadnes et al., 2002; Mayfield et al., 2012); 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: 27959664, 12124992, 29326875, 22267502) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 02, 2017 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 109 of the CBS protein (p.Cys109Arg). This variant is present in population databases (rs778220779, gnomAD 0.003%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12124992). 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: 212878). 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: 12124992, 22267502). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 13, 2014 | - - |
Homocystinuria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 26, 2016 | Variant summary: The c.325T>C in CBS gene is a missense variant that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is absent from the broad control population dataset of ExAC, suggesting this variant is not a common polymorphism. The variant has been reported in several affected individuals presented with features suggestive of Cystathionine--synthase deficiency. Functional studies performed in yeast-based system showed conflicting results in experiments with B6 supplementation, low enzymatic activity and non-functional yeast phenotype. The variant of interest has been reported as Pathogenic by several reputable databases/diagnostic centers without providing evidence to independently evaluate. Taking together, the variant was classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at