Submissions for variant NM_000537.4(REN):c.267G>T (p.Glu89Asp)

gnomAD frequency: 0.00001  dbSNP: rs886045835

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000266537	SCV000353467	uncertain significance	Familial juvenile hyperuricemic nephropathy type 2	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.
Illumina Laboratory Services, Illumina	RCV000305365	SCV000353468	uncertain significance	Renal tubular dysgenesis	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.
Fulgent Genetics, Fulgent Genetics	RCV002494915	SCV002781943	uncertain significance	Familial juvenile hyperuricemic nephropathy type 2; Renal tubular dysgenesis of genetic origin	2024-04-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003546500	SCV004268417	uncertain significance	not provided	2024-08-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 89 of the REN protein (p.Glu89Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with REN-related conditions. ClinVar contains an entry for this variant (Variation ID: 294963). 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 not expected to disrupt REN protein function with a negative predictive value of 80%. 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	RCV004021415	SCV004939047	uncertain significance	Inborn genetic diseases	2024-01-09	criteria provided, single submitter	clinical testing	The c.267G>T (p.E89D) alteration is located in exon 3 (coding exon 3) of the REN gene. This alteration results from a G to T substitution at nucleotide position 267, causing the glutamic acid (E) at amino acid position 89 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003957541	SCV004785535	uncertain significance	REN-related disorder	2024-02-28	no assertion criteria provided	clinical testing	The REN c.267G>T variant is predicted to result in the amino acid substitution p.Glu89Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.