ClinVar Miner

Submissions for variant NM_001017995.3(SH3PXD2B):c.1291G>A (p.Ala431Thr)

gnomAD frequency: 0.00041  dbSNP: rs142779141
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000174500 SCV000225810 uncertain significance not provided 2015-02-06 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001155394 SCV001316820 uncertain significance Frank-Ter Haar syndrome 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000174500 SCV001570960 uncertain significance not provided 2022-08-03 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 431 of the SH3PXD2B protein (p.Ala431Thr). This variant is present in population databases (rs142779141, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with SH3PXD2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 194189). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 RCV003317126 SCV004020760 uncertain significance not specified 2023-06-13 criteria provided, single submitter clinical testing Variant summary: SH3PXD2B c.1291G>A (p.Ala431Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251358 control chromosomes in GnomAD. c.1291G>A has not been reported in the literature in individuals affected with Frank-Ter Haar Syndrome, however, it has been reported as a non-informative genotype (zygosity/second allele not specified) in an individual with Axenfeld-Reiger syndrome (Mao_2012), which has an overlapping clinical spectrum with Frank-Ter Haar Syndrome. Statistical analysis failed to support a pathogenic role for SH3PXD2B variants in three forms of glaucoma, namely primary congenital glaucoma, Axenfeld-Rieger syndrome and primary open angle glaucoma as reported in this study. These report(s) do not provide unequivocal conclusions about association of the variant with Frank-Ter Haar Syndrome and/or SH3PXD2B-spectrum of disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22509100). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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