ClinVar Miner

Submissions for variant NM_015474.3(SAMHD1):c.1343T>C (p.Ile448Thr) (rs774964432)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657877 SCV000779639 likely pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing The I448T variant in the SAMHD1 gene has been previously reported in an individual with Aicardi-Goutieres syndrome who also harbored a second missense SAMHD1 variant, although the phase of these two variants was not confirmed (Rice et al., 2013). The I448T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The I448T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, and functional studies demonstrate that the I448T variant results in a protein with inability to block HIV-1 infection (White et al., 2017). We interpret I448T as a likely pathogenic variant.
Invitae RCV001242221 SCV001415292 uncertain significance Aicardi Goutieres syndrome 5 2019-04-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 448 of the SAMHD1 protein (p.Ile448Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. 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: 24183309). ClinVar contains an entry for this variant (Variation ID: 546088). This variant has been reported to affect SAMHD1 protein function (PMID: 28229507). 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.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV001242221 SCV001423610 likely pathogenic Aicardi Goutieres syndrome 5 2018-09-25 criteria provided, single submitter clinical testing [ACMG/AMP: PM2, PM3, PP3, PP4] This alteration is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], is predicted to be damaging by multiple functional prediction tools [PP3], is highly specific to for a disease with a single genetic etiology [PP4].

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