ClinVar Miner

Submissions for variant NM_000401.3(EXT2):c.344A>C (p.Asp115Ala) (rs534539796)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000328182 SCV000371828 likely benign Multiple exostoses type 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000328182 SCV001380961 uncertain significance Multiple exostoses type 2 2019-09-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 82 of the EXT2 protein (p.Asp82Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs534539796, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 304575). 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: Deleterious; PolyPhen-2: Benign; 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355388 SCV001550262 uncertain significance not provided no assertion criteria provided clinical testing The EXT2 p.Asp115Ala variant was not identified in the literature but was identified in dbSNP (ID: rs534539796) and ClinVar (classified as likely benign by Illumina). The variant was identified in control databases in 14 of 251264 chromosomes at a frequency of 0.00005572 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the South Asian population in 14 of 30614 chromosomes (freq: 0.000457), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), or Other populations. The p.Asp115 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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