ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.982G>A (p.Asp328Asn) (rs758447354)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665455 SCV000789584 uncertain significance Classic homocystinuria 2017-02-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755891 SCV000883538 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing The CBS c.982G>A; p.Asp328Asn variant (rs758447354) has been described in the compound heterozygous state in one individual with homocystinuria due to cystathionine beta-synthase deficiency (Silao 2015) and is observed in the general population at a low overall frequency of 0.0008% (2/245840 alleles) in the Genome Aggregation Database. The aspartic acid at codon 328 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Silao C et al. Novel cystathionine beta-synthase gene mutations in a Filipino patient with classic homocystinuria. Pediatr Int. 2015 Oct;57(5):884-7.
Invitae RCV000665455 SCV001392188 uncertain significance Classic homocystinuria 2019-06-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 328 of the CBS protein (p.Asp328Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs758447354, ExAC 0.01%). This variant has been observed in an individual affected with homocystinuria due to CBS deficiency (PMID: 25939784). ClinVar contains an entry for this variant (Variation ID: 550653). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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