Submissions for variant NM_001033855.3(DCLRE1C):c.419C>T (p.Ala140Val)

gnomAD frequency: 0.00056  dbSNP: rs41297016

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000543418	SCV004810420	likely benign	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-04-01	reviewed by expert panel	curation	The c.419C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Alanine by Valine at amino acid 140 (p.Ala140Val). The filtering allele frequency (the lower threshold of the 95% CI of 138/75030 alleles) of the c.419C>T variant in DCLRE1C is 0.001589 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00078) for BS1, and therefore meets this criterion (BS1). No homozygotes have been observed in gnomAD. To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 (VCEP specifications version 1.0).
GeneDx	RCV000487367	SCV000564931	uncertain significance	not provided	2016-06-15	criteria provided, single submitter	clinical testing	The A140V variant in the DCLRE1C gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A140V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000543418	SCV000645227	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 140 of the DCLRE1C protein (p.Ala140Val). This variant is present in population databases (rs41297016, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 418159). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.	RCV001272393	SCV001454377	uncertain significance	Histiocytic medullary reticulosis	2020-04-13	no assertion criteria provided	clinical testing