ClinVar Miner

Submissions for variant NM_015474.3(SAMHD1):c.1324C>T (p.Arg442Ter) (rs369587937)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000114347 SCV000814779 pathogenic Aicardi Goutieres syndrome 5 2018-05-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg442*) in the SAMHD1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Aicardi-Goutieres syndrome (PMID: 19525956). ClinVar contains an entry for this variant (Variation ID: 126406). Loss-of-function variants in SAMHD1 are known to be pathogenic (PMID: 19525956, 22461318). Experimental studies have shown that this nonsense change disrupts protein function (PMID: 22461318, 28229507). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000114347 SCV000915940 uncertain significance Aicardi Goutieres syndrome 5 2017-04-28 criteria provided, single submitter clinical testing The SAMHD1 c.1324C>T (p.Arg442Ter) variant is a stop-gained variant that is predicted to cause premature termination of the protein. The p.Arg442Ter variant has been reported in one study in which it is found in one patient with Aicardi-Goutieres syndrome in a compound heterozygous state with a missense variant (Rice et al. 2009). Control data are unavailable for this variant, which is also not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Functional studies with the p.Arg442Ter variant transfected into HEK293 cells demonstrate that the variant does not affect the RNA binding function of the protein (Goncalves et al. 2012). Based on the limited evidence and the potential impact of stop-gained variants, the p.Arg442Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for Aicardi-Goutieres syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneReviews RCV000114347 SCV000147923 pathogenic Aicardi Goutieres syndrome 5 2014-03-13 no assertion criteria provided literature only

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