Submissions for variant NM_001033855.3(DCLRE1C):c.406G>A (p.Asp136Asn)

dbSNP: rs1839765652

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001349774	SCV004102783	likely pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2023-11-14	reviewed by expert panel	curation	The NM_001033855.3:c.406G>A variant in DCLRE1C is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 136 (p.Asp136Asn). This variant is absent from population databases (gnomAD v2.2.1) (PM2_Supporting) and has been observed in two probands with SCID that carried a co-occurring variant in trans. The first proband has a clinical diagnosis of severe combined immunodeficiency (SCID) (0.5p) with a T-B-NK+ immunophenotype (0.5p) who was tested using a large 407 gene immunodeficiency panel (0.5p) and carried a co-occurring variant (c.629del p.Tyr210Leufs*14) in trans (Invitae, PP4 1.5p). The second proband is patient ART007 reported in PMID: 36566626, who has a clinical diagnosis of Artemis-related SCID (0.5p) that was corrected by DLCRE1C lentiviral gene therapy (1p) and carried a co-occurring variant (Deletion of exons 1-5) in trans (PP4 1.5p). For both patients, the co-occurring variant was confirmed in trans and would be classified as Likely Pathogenic or Pathogenic (PM3_Strong, 2p (1p per proband)). An in vitro study reported that this variant exhibited < 25% of wildtype V(D)J recombinase activity as well as undetectable endonucleolytic cleavage activity in an in vitro cleavage assay (PMID: 15071507, PS3_Moderate). In summary, this variant is classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied, PP4, PM3_Strong, PS3_Moderate, PM2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001267665	SCV001445892	likely pathogenic	Severe combined immunodeficiency disease	2019-07-10	criteria provided, single submitter	clinical testing	Although this variant has not been reported in an affected patient in the literature, the p.Asp136Asn variant has been mutated in an in vitro and in vivo model. The experiments showed that the Asp136Asn mutatant's ability to support V(D)J recombination was abolished (PMID: 15071507). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.406G>A (p.Asp136Asn) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.406G>A (p.Asp136Asn) variant is classified as Likely Pathogenic.
Invitae	RCV001349774	SCV001544134	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 136 of the DCLRE1C protein (p.Asp136Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (Invitae). 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: 986350). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Natera, Inc.	RCV001835359	SCV002078328	uncertain significance	Athabaskan severe combined immunodeficiency	2021-03-23	no assertion criteria provided	clinical testing