Submissions for variant NM_001034850.3(RETREG1):c.796C>T (p.Arg266Cys)

gnomAD frequency: 0.00006  dbSNP: rs368759467

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001002203	SCV000456168	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2B	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.
GeneDx	RCV000523712	SCV000620083	uncertain significance	not provided	2024-06-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002203	SCV001160077	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2B	2018-11-20	criteria provided, single submitter	clinical testing	The FAM134B c.796C>T; p.Arg266Cys variant (rs368759467), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 352691). This variant is found in the general population with an overall allele frequency of 0.0093% (26/280,424 alleles) in the Genome Aggregation Database. The arginine at codon 266 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg266Cys variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523712	SCV001220410	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 266 of the RETREG1 protein (p.Arg266Cys). This variant is present in population databases (rs368759467, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RETREG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 352691). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine 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.
Ambry Genetics	RCV002461100	SCV002754923	uncertain significance	Inborn genetic diseases	2020-12-04	criteria provided, single submitter	clinical testing	The p.R266C variant (also known as c.796C>T), located in coding exon 6 of the FAM134B gene, results from a C to T substitution at nucleotide position 796. The arginine at codon 266 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.