ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.919G>A (p.Gly307Ser) (rs121964962)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618753 SCV000738476 pathogenic Cardiovascular phenotype 2017-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000173641 SCV000485254 pathogenic Homocystinuria due to CBS deficiency 2015-11-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078112 SCV000224773 pathogenic not provided 2014-11-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000173641 SCV000893554 pathogenic Homocystinuria due to CBS deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000078112 SCV000249696 pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing The pathogenic G307S missense variant in the CBS gene is a common variant found on approximately 70% of alleles in patients of Celtic origin with homocystinuria due to CBS deficiency and is usually associated with a more severe non-B6 responsive phenotype (Urreizti et al., 2006). Functional studies shave shown that G307S is located in the catalytic site and leads to increased protein unfolding, a shift towards unfolded intermediates and a significant decrease in enzyme activity in comparison to wild-type (Kozich et al., 2010; Hnizda et al., 2012). Furthermore, while the G307S variant is observed in 39/126706 (0.03%) alleles from individuals of European (Non-Finnish) ancestry, there are no homozygous individuals present in large population cohorts (Lek et al., 2016). The G307S 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. Finally, this substitution occurs at a position that is conserved in species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Illumina Clinical Services Laboratory,Illumina RCV000173641 SCV000436215 pathogenic Homocystinuria due to CBS deficiency 2017-04-27 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000366433 SCV000695310 pathogenic Homocystinuria 2017-04-06 criteria provided, single submitter clinical testing 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.
Invitae RCV000173641 SCV000543511 pathogenic Homocystinuria due to CBS deficiency 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 307 of the CBS protein (p.Gly307Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs121964962, ExAC 0.03%). This variant is clearly defined as a causative allele for homocystinuria and has been observed in multiple affected individuals (PMID: 8744616, 7506602, 7581402, 9889017, 23733603). ClinVar contains an entry for this variant (Variation ID: 117). Experimental studies have shown that this missense change significantly disrupts CBS protein structure and enzymatic activity (PMID: 20506325, 22267502). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000173641 SCV000711669 pathogenic Homocystinuria due to CBS deficiency 2015-12-15 criteria provided, single submitter clinical testing The p.Gly307Ser variant in CBS has been reported in at least 3 homozygote and 1 compound heterozygote probands with homocystinuria and segregated with disease i n 5 affected family members (Hu 1993, Dawson 1996, Stabler 2013). In addition, i n vitro functional studies provide evidence that the variant leads to impaired p rotein function (Hu 1993, Hnizda 2012, Kozich 2010, Mayfield 2012). This variant has also been identified in 17/66640 of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121964962). Alt hough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this va riant meets our criteria to be classified as pathogenic for homocystinuria in an autosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) b ased upon its segregation in affected individuals and functional evidence.
OMIM RCV000000137 SCV000020280 pathogenic Homocystinuria, pyridoxine-nonresponsive 2003-01-28 no assertion criteria provided literature only
OMIM RCV000000138 SCV000020281 pathogenic HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED 2003-01-28 no assertion criteria provided literature only

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