ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1039G>A (p.Gly347Ser) (rs771298943)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169132 SCV000220343 likely pathogenic Homocystinuria due to CBS deficiency 2014-05-22 criteria provided, single submitter literature only
GeneDx RCV000197584 SCV000249703 pathogenic not provided 2015-06-29 criteria provided, single submitter clinical testing The G347S mutation in the CBS gene has been reported multiple times in patients with homocystinuria due to CBS deficiency (Gaustadnes et al. 2002; Zschocke et al. 2009; Katsushima et al. 2006; Karaca et al. 2014; Zaidi et al. 2012; Lee et al. 2005). Expression studies found that G347S is associated with very low levels of residual cystathionine beta-synthase enzyme activity compared to wild-type (Gaustadnes et al. 2002; Lee et al. 2005). A patient homozygous for G347S is reported to be vitamin B6 responsive (Katsushima et al. 2006). This variant was found in CBS,TAAD
Integrated Genetics/Laboratory Corporation of America RCV000780082 SCV000917108 pathogenic Homocystinuria 2018-12-14 criteria provided, single submitter clinical testing Variant summary: CBS c.1039G>A (p.Gly347Ser) 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 3.2e-05 in 30882 control chromosomes. c.1039G>A has been reported in the literature in multiple individuals affected with Homocystinuria (Gaustadnes_2002, Lee_2005, Katsushima_2006, Karaca_2014, Yubero_2016). 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 <10% of normal activity (Lee_2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169132 SCV000937630 pathogenic Homocystinuria due to CBS deficiency 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 347 of the CBS protein (p.Gly347Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 11 of the CBS coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous or in combination with another CBS variant in several individuals affected with homocystinuria (PMID: 12124992, 16205833, 16307898, 19370759, 24211323). ClinVar contains an entry for this variant (Variation ID: 188801). Experimental studies have shown that this missense change disrupts CBS protein function (PMID: 22267502). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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