Submissions for variant NM_001033855.3(DCLRE1C):c.169G>T (p.Val57Phe)

gnomAD frequency: 0.00016  dbSNP: rs138077101

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000644807	SCV004102788	likely benign	Severe combined immunodeficiency due to DCLRE1C deficiency	2023-11-14	reviewed by expert panel	curation	The c.169G>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause a substitution of Valine by Phenylalanine at amino acid 57 (p.Val57Phe). The popmax filtering allele frequency in gnomAD v2.1. is 0.0001675 (based on 29/128916 alleles in the non-Finnish European population), which is below the SCID VCEP established threshold of >0.00078. However, the highest MAF is in the Ashkenazi Jewish population at 0.005896 (61/10346 alleles and NO homozygotes reported), which is above the SCID VCEP established threshold of >00078. As this population is not known to have a higher disease prevalence, this is considered to meet BS1. After a comprehensive literature search, the variant has not been found in individuals with SCID due to DCLRE1C deficiency. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Illumina Laboratory Services, Illumina	RCV000261164	SCV000361562	uncertain significance	Histiocytic medullary reticulosis	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644807	SCV000766522	likely benign	Severe combined immunodeficiency due to DCLRE1C deficiency	2025-01-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000261164	SCV001712296	uncertain significance	Histiocytic medullary reticulosis	2021-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002520545	SCV003541047	uncertain significance	Inborn genetic diseases	2022-09-28	criteria provided, single submitter	clinical testing	The c.169G>T (p.V57F) alteration is located in exon 3 (coding exon 3) of the DCLRE1C gene. This alteration results from a G to T substitution at nucleotide position 169, causing the valine (V) at amino acid position 57 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001272394	SCV001454378	uncertain significance	Athabaskan severe combined immunodeficiency	2020-04-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003940129	SCV004752339	likely benign	DCLRE1C-related disorder	2019-07-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).