ClinVar Miner

Submissions for variant NM_002351.5(SH2D1A):c.118G>A (p.Val40Met)

gnomAD frequency: 0.00009  dbSNP: rs199639961
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001224587 SCV001396795 uncertain significance X-linked lymphoproliferative disease due to SH2D1A deficiency 2023-10-18 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 40 of the SH2D1A protein (p.Val40Met). This variant is present in population databases (rs199639961, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with SH2D1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 952469). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001224587 SCV002584681 uncertain significance X-linked lymphoproliferative disease due to SH2D1A deficiency 2022-09-28 criteria provided, single submitter clinical testing The SH2D1A c.118G>A (p.Val40Met) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with X-linked lymphoproliferative disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics RCV002339601 SCV002640408 uncertain significance Inborn genetic diseases 2022-08-22 criteria provided, single submitter clinical testing The p.V40M variant (also known as c.118G>A), located in coding exon 1 of the SH2D1A gene, results from a G to A substitution at nucleotide position 118. The valine at codon 40 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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