Submissions for variant NM_015474.4(SAMHD1):c.602T>A (p.Ile201Asn)

gnomAD frequency: 0.00002  dbSNP: rs138603088

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, 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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000023578	SCV000937623	pathogenic	Aicardi-Goutieres syndrome 5	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 201 of the SAMHD1 protein (p.Ile201Asn). This variant is present in population databases (rs138603088, gnomAD 0.005%). This missense change has been observed in individuals with SAMHD1-related conditions (PMID: 19525956, 20653736, 27604406). ClinVar contains an entry for this variant (Variation ID: 30605). 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: 22461318, 22973040, 28229507). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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.
GeneDx	RCV001555533	SCV001776971	pathogenic	not provided	2020-09-16	criteria provided, single submitter	clinical testing	Observed in the heterozygous state without a second SAMHD1 variant identified in a mother and son with familial chilblain lupus in the published literature (Ravenscroft et al., 2011); Published functional studies demonstrate a damaging effect through altered cellular localization, reduced protein expression, and catalytic inactivity (Goncalves et al., 2012; Hofmann et al., 2012; White et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21204240, 20653736, 30275001, 27604406, 22149989, 24335234, 25604658, 22639057, 22973040, 28229507, 19525956, 22461318, 22953710, 24035396, 22691373, 24183309)
Revvity Omics, Revvity	RCV001555533	SCV002019987	pathogenic	not provided	2022-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825545	SCV005204113	pathogenic	Aicardi Goutieres syndrome	2024-06-21	criteria provided, single submitter	clinical testing	Variant summary: SAMHD1 c.602T>A (p.Ile201Asn) results in a non-conservative amino acid change located in the HD/PDEase domain (IPR003607) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251364 control chromosomes. c.602T>A has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Aicardi Goutieres Syndrome (e.g. Ramesh_2010, Haskell_2018, Yarbrough_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly reduced ability to block viral infection in transfected U937 cells (White_2017). The following publications have been ascertained in the context of this evaluation (PMID: 30275001, 20653736, 28229507, 27604406). ClinVar contains an entry for this variant (Variation ID: 30605). Based on the evidence outlined above, the variant was classified as pathogenic.
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	not provided	Aicardi-Goutieres syndrome 5		no assertion provided	literature only
Natera, Inc.	RCV000825545	SCV002090996	pathogenic	Aicardi Goutieres syndrome	2020-12-02	no assertion criteria provided	clinical testing