Submissions for variant NM_001033855.3(DCLRE1C):c.95C>G (p.Ser32Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003062252	SCV004242280	likely pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-01-23	reviewed by expert panel	curation	The c.95C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 32 (p.Ser32Cys). The highest population minor allele frequency in gnomAD v.4 is 0.00002236 (1/44722 alleles) in Latino/Admixed American population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant, c.95C>T; p.Ser32Phe, ClinVar Variation ID: 1438811, in the same codon, has been classified as likely pathogenic for SCID by the ClinGen SCID VCEP (PM5_Supporting). The variant was identified in two patients in the literature (PubMed IDs 25917813, 15242402, and PMID: 35886058. The patient reported in Rosina E et al. presents: Diagnostic criteria for SCID 0.5 pts + SCID gene panel or exome/genome sequencing conducted 0.5pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total is 1.5 points, PP4_Supporting. This same patient is homozygous for the variant: 0.5 pts, PM3_Supporting (PMID: 35886058). Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.4) and DNA repair (36h after IR): Mean (SD): 6.56 (8.73). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level (PMID: 25917813). In summary, this variant is classified as Likely Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PM5_Supporting, PP4_Supporting, PM3_Supporting, and PS3_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003062252	SCV003441411	likely pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 32 of the DCLRE1C protein (p.Ser32Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 15242402, 25917813, 35886058; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2136852). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DCLRE1C function (PMID: 25917813). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.