ClinVar Miner

Submissions for variant NM_015474.4(SAMHD1):c.427C>T (p.Arg143Cys)

gnomAD frequency: 0.00001  dbSNP: rs387906948
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000023577 SCV003443372 likely pathogenic Aicardi-Goutieres syndrome 5 2023-09-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 143 of the SAMHD1 protein (p.Arg143Cys). This variant is present in population databases (rs387906948, gnomAD 0.0009%). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 19525956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30604). 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. Experimental studies have shown that this missense change affects SAMHD1 function (PMID: 26431200, 28229507). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, 28229507, 29379009, 33683010; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000023577 SCV000044868 pathogenic Aicardi-Goutieres syndrome 5 2009-07-01 no assertion criteria provided literature only
GeneReviews RCV000023577 SCV000147930 not provided Aicardi-Goutieres syndrome 5 no assertion provided literature only

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