ClinVar Miner

Submissions for variant NM_015474.4(SAMHD1):c.428G>A (p.Arg143His)

gnomAD frequency: 0.00001  dbSNP: rs369035155
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000114352 SCV001373235 pathogenic Aicardi-Goutieres syndrome 5 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 143 of the SAMHD1 protein (p.Arg143His). This variant is present in population databases (rs369035155, gnomAD 0.004%). This missense change has been observed in individuals with Aicardi-Goutières syndrome (PMID: 19525956, 33683010; Invitae). ClinVar contains an entry for this variant (Variation ID: 126411). 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 SAMHD1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SAMHD1 function (PMID: 28229507, 29379009). This variant disrupts the p.Arg143 amino acid residue in SAMHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19525956, 26431200, 28229507). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital RCV000114352 SCV001423609 pathogenic Aicardi-Goutieres syndrome 5 2018-09-25 criteria provided, single submitter clinical testing [ACMG/AMP: PS3, PM2, PM5, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
AiLife Diagnostics, AiLife Diagnostics RCV002223787 SCV002502603 likely pathogenic not provided 2022-03-22 criteria provided, single submitter clinical testing
GeneDx RCV002223787 SCV005201559 pathogenic not provided 2023-12-19 criteria provided, single submitter clinical testing Published functional studies demonstrate that this variant has a damaging effect and leads to a loss of protein function (PMID: 28229507); This variant is associated with the following publications: (PMID: 19525956, 30487145, 23364794, 22056990, 22149989, 34055681, 33683010, 27943079, 29379009, 28229507, 32371413)
GeneReviews RCV000114352 SCV000147931 not provided Aicardi-Goutieres syndrome 5 no assertion provided literature only

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