Submissions for variant NM_001034850.3(RETREG1):c.380G>A (p.Arg127His)

gnomAD frequency: 0.00036  dbSNP: rs200871433

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657003	SCV000516111	uncertain significance	not provided	2024-08-22	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000527046	SCV000603537	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2B	2019-05-03	criteria provided, single submitter	clinical testing	The RETREG1 c.380G>A; p.Arg127His variant (rs200871433) has not been reported in the medical literature; however, this variant is listed in the ClinVar database as uncertain (Variation ID: 379338). This variant is found in the general population with an allele frequency in non-Finnish European populations of 0.05% (61/128,652 alleles) in the Genome Aggregation Database. The arginine at codon 127 is highly conserved (Alamut v.2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, based on the available information, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657003	SCV000648503	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 127 of the FAM134B protein (p.Arg127His). This variant is present in population databases (rs200871433, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FAM134B-related conditions. ClinVar contains an entry for this variant (Variation ID: 379338). 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.
Illumina Laboratory Services, Illumina	RCV000527046	SCV001317945	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2B	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657003	SCV001714137	uncertain significance	not provided	2019-06-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002461142	SCV002754922	likely benign	Inborn genetic diseases	2024-01-02	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.