Submissions for variant NM_000536.4(RAG2):c.501A>C (p.Arg167Ser)

dbSNP: rs1159686210

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765345	SCV005375457	uncertain significance	Recombinase activating gene 2 deficiency	2024-05-14	reviewed by expert panel	curation	The c.501A>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Arginine by Serine at amino acid 167 (p.Arg167Ser). The highest population minor allele frequency in gnomAD v4 is 0.0001941 (1/5152 alleles) in the Ashkenazi Jewish population. As this is a known bottleneck population, it will not be considered here for PM2_Supporting. As no other alleles have been reported in other populations, PM2 at the supporting level is applied (Absence in GnomAD). This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting. This variant has been detected in one individual with SCID, reported by Invitae in ClinVar. This individual is compound heterozygous for p.Gly95Arg, a likely pathogenic variant according to SCID VCEP specifications. Both parents were tested, and the phase is confirmed: 1 point. PM3_Moderate (Internal lab contributor). No clinical features were described; Not possible to evaluate for PP4. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PM1_Supporting, and PM3_Moderate. (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001062677	SCV001227492	likely pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-04-02	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG2 protein function. This variant has been observed in individual(s) with severe combined immunodeficiency (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 857069). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 167 of the RAG2 protein (p.Arg167Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193857	SCV001363007	uncertain significance	not specified	2019-02-25	criteria provided, single submitter	clinical testing	Variant summary: RAG2 c.501A>C (p.Arg167Ser) 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 245916 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.501A>C has been reported in at-least one newborn with a confirmed diagnosis of Severe Combined Immunodeficiency Syndrome in addition to its identification in a patient tested at our laboratory. However, as these observations have not been reported in the peer-reviewed literature, these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001274397	SCV001458521	uncertain significance	Histiocytic medullary reticulosis	2020-01-24	no assertion criteria provided	clinical testing