ClinVar Miner

Submissions for variant NM_015474.3(SAMHD1):c.602T>A (p.Ile201Asn) (rs138603088)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000284100 SCV000433786 uncertain significance Chilblain Lupus 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000023578 SCV000433787 likely pathogenic Aicardi Goutieres syndrome 5 2017-04-27 criteria provided, single submitter clinical testing The SAMHD1 c.602T>A (p.Ile201Asn) variant has been reported in at least three studies in which it was found in a homozygous state in two individuals, in a compound heterozygous state in one individual, and in a heterozygous state in four individuals, all with Aicardi-Goutieres syndrome (Rice et al. 2009; Ramesh et al. 2010; Crow et al. 2015). In one of these families, the variant was reported to cosegregate with disease. The p.Ile201Asn variant was absent from 450 control alleles (Ravenscroft et al. 2011) and is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in HEK 293T cells showed that the variant resulted in reduced protein expression compared to wildtype and catalytic inactivity (Hofmann et al. 2012). Localization studies for the variant protein are conflicting; Hofmann et al. (2012) reported a normal nuclear localization in HEK 293T cells compared to wild type whereas Goncalves et al. (2012) reported cytosolic localization of the variant protein in HeLa cells. Based on the collective evidence, the p.Ile201Asn variant is classified as likely pathogenic for Aicardi-Goutieres syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000023578 SCV000803284 likely pathogenic Aicardi Goutieres syndrome 5 2018-08-06 criteria provided, single submitter research The SAMHD1 Ile201Asn (p.I201N) variant has previously been reported in two unrelated individuals with autosomal recessive Aicardi-Goutieres syndrome 5, along with a second deleterious variant (Rice 2009, PMID: 19525956; Ramesh 2010, PMID: 20653736). It is located within the HD (histidine-aspartate) domain of the encoded protein and was observed in 6/111618 alleles in the GnomAD European (Non-Finnish) population (allele frequency 0.00005). This variant has a score of 0.901 by the REVEL metapredictor (Ioannidis 2016, PMID: 27666373), which exceeds the ClinGen threshold cut-off (0.75) for application of ACMG/AMP in silico prediction evidence. This variant was observed in trans with a second missense variant (Leu431Phe), which is classified as a VUS, in a patient with symptoms highly consistent with Aicardi-Goutieres syndrome. In summary, the Ile201Asn variant meets ACMG/AMP criteria to be classified as likely pathogenic (PM1, PM2, PP3, PP4).
Invitae RCV000023578 SCV000937623 pathogenic Aicardi Goutieres syndrome 5 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 201 of the SAMHD1 protein (p.Ile201Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs138603088, ExAC 0.004%). This variant has been observed in several individuals affected with SAMHD1-related conditions (PMID: 19525956, 20653736, 27604406). ClinVar contains an entry for this variant (Variation ID: 30605). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 22461318, 28229507, 22973040). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825545 SCV000966862 likely pathogenic Aicardi Goutieres syndrome 2018-12-17 criteria provided, single submitter clinical testing The p.Ile201Asn variant in SAMHD1 has been reported in 4 individuals with Aicard i-Goutieres syndrome: 1 who was homozygous for the variant, 2 who carried additi onal rare missense variants in SAMHD1, and 1 who also carried a frameshift varia nt in SAMHD1 (Rice 2009, Ramesh 2010, Yarbrough 2016, Haskell 2018). It segregat ed with disease in 2 affected individuals from 1 family who had symptoms of Aica rdi-Goutieres syndrome but did not have neurological involvement (Yarbrough 2016 ). In addition, it was identified in the heterozygous state in a mother and son with early onset chilblain lupus (Ravenscroft 2010). It has also been identified in 6/113690 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org ) and reported in ClinVar (Variation ID # 30605). In summary, although additiona l studies are required to fully establish its clinical significance, this varian t meets criteria to be classified as likely pathogenic for autosomal recessive A icardi-Goutieres syndrome. ACMG/AMP criteria applied: PM2, PM3, PP1_Moderate, PP 3, PS3_Supporting.
OMIM RCV000023578 SCV000044869 pathogenic Aicardi Goutieres syndrome 5 2015-02-01 no assertion criteria provided literature only
OMIM RCV000023579 SCV000044870 pathogenic Chilblain lupus 2 2015-02-01 no assertion criteria provided literature only
GeneReviews RCV000023578 SCV000147935 pathogenic Aicardi Goutieres syndrome 5 2014-03-13 no assertion criteria provided literature only

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