ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.194C>T (p.Thr65Ile)

dbSNP: rs886037925
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV000240844 SCV004102787 pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2023-11-14 reviewed by expert panel curation The c.194C>T(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 65 p.Thr65Ile. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been detected in at least 13 individuals with SCID/Lealy SCID/Omen. Of those individuals, 2 were compound heterozygous for the variant p.T577Nfs*21 (Likely Pathogenic according to the SCID VCEP specifications - confirmed in trans by family testing (PMID: 26476407, 2 pts). 10 individuals were homozygous for the variant (1 point limit was reached - PMID: 26476407) (PM3_moderate); For 1 individual (PMID: 25917813), the second allele information wasn't available. The variant has been reported to segregate with SCID in 7 affected family members from 3 families (Family A: Proband + 4; Family D: Proband + 2; Family E: Proband + 1 = 7 segregations, LOD: 4.21); PP1_Strong; PMID: 26476407). At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P1, 2 and 5, 2 pts, PMID:26476407, PP4_moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, PP4_Moderate, PP1_Strong, PM3_Strong, PM2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Invitae RCV000240844 SCV004295641 pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2023-09-03 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 65 of the DCLRE1C protein (p.Thr65Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 25917813, 26476407, 27577878). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 254217). 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 not expected to disrupt DCLRE1C protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DCLRE1C function (PMID: 25917813). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000240844 SCV000299330 pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2016-09-14 no assertion criteria provided literature only

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