ClinVar Miner

Submissions for variant NM_000112.4(SLC26A2):c.764G>A (p.Gly255Glu)

gnomAD frequency: 0.00003  dbSNP: rs104893917
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000675076 SCV000800572 uncertain significance Multiple epiphyseal dysplasia type 4 2017-07-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001851640 SCV002257003 uncertain significance Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia 2022-07-05 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 255 of the SLC26A2 protein (p.Gly255Glu). This variant is present in population databases (rs104893917, gnomAD 0.01%). This missense change has been observed in individual(s) with atelosteogenesis type II (PMID: 8571951). ClinVar contains an entry for this variant (Variation ID: 4090). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A2 protein function. Experimental studies have shown that this missense change affects SLC26A2 function (PMID: 11448940). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230347 SCV003928789 likely pathogenic Osteochondrodysplasia 2023-04-06 criteria provided, single submitter clinical testing Variant summary: SLC26A2 c.764G>A (p.Gly255Glu) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251356 control chromosomes. c.764G>A has been reported in the literature in an individual affected with Atelosteogenesis type II (Hastbacka_1996), and they were repoted as compound heterozygous with a variant that one ClinVar submitter has classified as pathogenic. These data suggest the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing <10% of normal DTDST-mediated sulfate uptake in Xenopus oocytes injected with cRNA containing the variant. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000004308 SCV000024475 pathogenic Atelosteogenesis type II 1996-02-01 no assertion criteria provided literature only

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