Submissions for variant NM_001025603.2(RFX5):c.1805G>A (p.Ser602Asn)

gnomAD frequency: 0.00004  dbSNP: rs371115213

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695303	SCV000823792	uncertain significance	MHC class II deficiency	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 602 of the RFX5 protein (p.Ser602Asn). This variant is present in population databases (rs371115213, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with RFX5-related conditions. ClinVar contains an entry for this variant (Variation ID: 573595). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Illumina Laboratory Services, Illumina	RCV000695303	SCV001255949	uncertain significance	MHC class II deficiency	2018-01-13	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.
Ambry Genetics	RCV004025237	SCV003706841	likely benign	not specified	2022-06-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003420234	SCV004109197	uncertain significance	RFX5-related disorder	2022-12-12	criteria provided, single submitter	clinical testing	The RFX5 c.1805G>A variant is predicted to result in the amino acid substitution p.Ser602Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-151314708-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.