ClinVar Miner

Submissions for variant NM_015474.4(SAMHD1):c.649_650insG (p.Phe217fs)

gnomAD frequency: 0.00001  dbSNP: rs515726146
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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 RCV000114354 SCV002157045 pathogenic Aicardi-Goutieres syndrome 5 2023-11-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe217Cysfs*2) in the SAMHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SAMHD1 are known to be pathogenic (PMID: 19525956, 22461318). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 20653736). ClinVar contains an entry for this variant (Variation ID: 126413). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina RCV000114354 SCV004014753 pathogenic Aicardi-Goutieres syndrome 5 2023-01-09 criteria provided, single submitter clinical testing The SAMHD1 c.649_650insG (p.Phe217CysfsTer2) variant results in the insertion of a nucleotide at position c.649, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. The variant has been reported in a compound heterozygous state with a known pathogenic deletion in one individual with Aicardi-Goutieres syndrome (PMID: 20653736). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000325 in the Ashkenazi Jewish population (version 3.1.2). The c.649_650insG variant lies in the HD domain of the protein which is reported to be involved in nucleotide binding (PMID: 22461318). Based on the available evidence, the c.649_650insG (p.Phe217CysfsTer2) variant is classified as pathogenic for Aicardi-Goutieres syndrome.
GeneReviews RCV000114354 SCV000147937 not provided Aicardi-Goutieres syndrome 5 no assertion provided literature only

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