21-43062988-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000071.3(CBS):c.919G>A(p.Gly307Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000071.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251400Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135886
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 46Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 26
GnomAD4 genome
ClinVar
Submissions by phenotype
Classic homocystinuria Pathogenic:8Other:1
The p.Gly307Ser variant in CBS has been reported in at least 11 homozygous, 4 compound heterozygous and 15 heterozygous (where the second variant has not been reported) probands with homocystinuria and segregated with disease in 5 affected family members (Hu 1993, Dawson 1996, Stabler 2013, Gallagher 1995, Moat 2004). It was also reported in 1 heterozygous individual with homocystinuria and reversible cerebral white matter abnormalities who was also heterozygous for the MTHFR c.677C>T variant (Ismayilova 2019). This variant has been reported in ClinVar (ClinVar ID 117). In addition, in vitro functional studies provide evidence that the variant leads to impaired protein function (Hu 1993, Hnizda 2012, Kozich 2010, Mayfield 2012). This variant has also been identified in 41/129158 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). However, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PM3_very_strong, PP1_strong, PS3_supporting. -
The c.919G>A (G307S) was identified in a patient of African & French Canadian origin in compound heterozygote with c.941G>C (V314A). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had a mild intellectual impairment and does not respond to treatment with vitamin B6. -
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The CBS c.919G>A (p.Gly307Ser) variant is well described as a common pathogenic allele in individuals with homocystinuria of Celtic origin, accounting for 71% of disease associated alleles in Ireland, 21% in the UK and 8% in the US (Moat et al. 2004). The presence of a single allele almost always predicts non-responsiveness to pyroxidine therapy. The p.Gly307Ser variant has been reported in at least six studies in which it is found in a total of 44 individuals including 14 in a homozygous state (including two pairs of siblings), ten in a compound heterozygous state (four of whom were related), and 20 heterozygotes in whom a second allele has not yet been identified (Hu et al. 1993; Gallagher et al. 1995; Kim et al. 1997; Kelly et al. 2003; Moat et al. 2004; Stabler et al. 2013). The variant was also found in at least three unaffected heterozygous relatives. The variant was absent from 82 control chromosomes but is reported at a frequency of 0.00026 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies have demonstrated that the Gly307 residue is located in the catalytic site of the protein and results in the production of correctly assembled tetramers that are slightly unfolded with a shift towards unfolded intermediates. The catalytic activity of the p.Gly307Ser variant protein is completely abolished (Hu et al. 1993; Hnizda et al. 2012). Based on the collective evidence, the p.Gly307Ser variant is classified as pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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NM_000071.2(CBS):c.919G>A(G307S) is classified as pathogenic in the context of CBS-related homocystinuria, and is associated with the B6-non-responsive form of this disease. Sources cited for classification include the following: PMID 9889017, 20506325, 7506602 and 22267502. Classification of NM_000071.2(CBS):c.919G>A(G307S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
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not provided Pathogenic:3
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Common pathogenic variant found on approximately 70% of alleles in patients of Celtic origin with homocystinuria due to cystathionine beta-synthase (CBS) deficiency and is usually associated with a more severe non-B6 responsive phenotype (Urreizti et al., 2006); Functional studies found that G307S is associated with significantly decreased CBS enzyme activity compared to wild-type (Hu et al. 1993; Kozich et al. 2010; Hnizda et al. 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 7581402, 14722927, 7564249, 17319270, 12552044, 8744616, 22267502, 23733603, 22069143, 7506602, 16479318, 30609409, 30187370, 12686134, 18280597, 12124992, 9361025, 25636110, 20506325) -
CBS: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting -
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:2
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CBS protein (p.Gly307Ser). This variant is present in population databases (rs121964962, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria (PMID: 7506602, 7581402, 8744616, 9889017, 23733603). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 117). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 20506325, 22267502). For these reasons, this variant has been classified as Pathogenic. -
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Homocystinuria, pyridoxine-nonresponsive Pathogenic:1
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The p.G307S pathogenic mutation (also known as c.919G>A), located in coding exon 8 of the CBS gene, results from a G to A substitution at nucleotide position 919. The glycine at codon 307 is replaced by serine, an amino acid with similar properties. This alteration was described to account for about 70% of disease alleles in Ireland (Gallagher PM et al. Hum. Mutat., 1995;6:177-80), 21% in UK and 8% in US (Moat SJ et al. Hum. Mutat., 2004 Feb;23:206). This alteration has been reported in the homozygous state in multiple individuals with homocysteinuria, as well as in the heterozygous state in patients with an (un)identified second allele (Dawson PA et al. Aust N Z J Med, 1996 Apr;26:180-5; Gallagher PM et al. Hum. Mutat., 1995;6:177-80; Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Moat SJ et al. Hum. Mutat., 2004 Feb;23:206). In addition, this alteration was reported to occur in the enzyme active site (Meier M et al. Biochim. Biophys. Acta, 2003 Apr;1647:206-13), and in vitro studies have consistently suggested that this change would abolish enzyme activity, probably by interfering with protein folding (Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Hnízda A et al. J. Inherit. Metab. Dis., 2012 May;35:469-77). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Homocystinuria Pathogenic:1
Variant summary: The CBS c.919G>A (p.Gly307Ser) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 19/121292 control chromosomes at a frequency of 0.0001566, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). This variant has been reported in many affected individuals and functional study showed variant with <1% activity in comparison with WT (Kozich_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
CBS-related disorder Pathogenic:1
The CBS c.919G>A variant is predicted to result in the amino acid substitution p.Gly307Ser. This variant is one of the most commonly reported CBS variants causative for homocystinuria due to cystathionine beta-synthase deficiency (e.g., Gallagher et al. 1995. PubMed ID: 7581402; Kraus et al. 1999. PubMed ID: 10338090). In experimental studies, the p.Gly307Ser substitution has been shown to greatly impair CBS enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at