Submissions for variant NM_001033855.3(DCLRE1C):c.95C>T (p.Ser32Phe)

dbSNP: rs969498121

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001965262	SCV004242281	likely pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-01-23	reviewed by expert panel	curation	The c.95C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Phenylalanine at amino acid 32 (p.Ser32Phe). The filtering allele frequency (the upper threshold of the 95% CI of 2/1111892 alleles) of the c.95C>T variant in DCLRE1C is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). At least one patient in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total 1 pt; Which is highly specific for SCID. PP4_Supporting (PMIDs: 18223550 and 25917813 - same patient). The proband is compound heterozygous, in trans, for del Ex1-3 (at least LP according to our SCID VCEP specifications;) 1 point, PM3_Moderate. (PMID: 25917813). Activity levels in % of WT activity = Recombination: Mean (SD): 5.14 (0.34) and DNA repair (36h after IR): Mean (SD): 20.95 (6.17). 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 a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Supporting, PM3_Moderate, and PS3_Moderate.
Invitae	RCV001965262	SCV002216201	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2021-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine with phenylalanine at codon 32 of the DCLRE1C protein (p.Ser32Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 18223550). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as C133T. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects DCLRE1C function (PMID: 25917813). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003471090	SCV004190904	likely pathogenic	Histiocytic medullary reticulosis	2024-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526885	SCV005040281	likely pathogenic	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2024-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004542188	SCV005040781	likely pathogenic	Aicardi-Goutieres syndrome 1	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: TREX1 c.95C>T (p.Thr32Met) results in a non-conservative amino acid change located in the Exonuclease, RNase T/DNA polymerase III domain (IPR013520) 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 2e-05 in 251328 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.95C>T has been reported in the literature in at-least one individual affected with early onset high myopia (eoHM) who underwent exome sequencing (eoHM) (example, Zhou_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Aicardi Goutieres Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004577007	SCV005061373	likely pathogenic	Severe combined immunodeficiency disease	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: DCLRE1C c.95C>T (p.Ser32Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes (gnomAD). c.95C>T has been reported in the literature in at least one compound heterozygous individual affected with Severe Combined Immunodeficiency (Lagresle-Peyrou_2008, Felgentreff_2015) who carried a (likely) pathogenic variant in trans. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in recombination activity ~5% and DNA repair activity ~21% of wild-type (Felgentreff_2015). In addition, a different missense affecting the same amino acid (p.S32C) has been reported in affected individuals (HGMD), indicating a functional importance for the Ser32 amino acid residue. The following publications have been ascertained in the context of this evaluation (PMID: 18223550, 25917813). ClinVar contains an entry for this variant (Variation ID: 1438811). Based on the evidence outlined above, the variant was classified as likely pathogenic.