ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.362G>A (p.Arg121His) (rs770095972)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169322 SCV000220655 likely pathogenic Classic homocystinuria 2014-08-28 criteria provided, single submitter literature only
Invitae RCV000169322 SCV001224398 pathogenic Classic homocystinuria 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 121 of the CBS protein (p.Arg121His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs770095972, ExAC 0.01%). This variant has been observed in several individuals affected with homocystinuria (PMID: 16479318, 16307898, 10338090). ClinVar contains an entry for this variant (Variation ID: 188948). This variant has been reported to affect CBS protein function (PMID: 16307898, 22267502). This variant disrupts the p.Arg121 amino acid residue in CBS. Other variant(s) that disrupt this residue have been observed in individuals with CBS-related conditions (PMID: 16307898, 21520339, 10338090, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001192720 SCV001361015 pathogenic Homocystinuria 2019-04-01 criteria provided, single submitter clinical testing Variant summary: CBS c.362G>A (p.Arg121His) 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 3.3e-05 in 276770 control chromosomes (gnomAD). c.362G>A has been reported in the literature in multiple individuals affected with Homocystinuria (Katsushima_2006, Urreizti_2006, Kraus_1999). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant enzyme to exhibit severely decreased activity and be devoid of correctly assembled tetramer (Katsushima_2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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