Submissions for variant NM_181882.3(PRX):c.3271G>A (p.Ala1091Thr)

gnomAD frequency: 0.00008  dbSNP: rs368459753

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094555	SCV000413209	uncertain significance	Charcot-Marie-Tooth disease type 4F	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554727	SCV000658012	uncertain significance	Charcot-Marie-Tooth disease type 4	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1091 of the PRX protein (p.Ala1091Thr). This variant is present in population databases (rs368459753, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 329257). 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 threonine 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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000857050	SCV001335838	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446591	SCV002611923	uncertain significance	Inborn genetic diseases	2023-10-25	criteria provided, single submitter	clinical testing	The c.3271G>A (p.A1091T) alteration is located in exon 7 (coding exon 4) of the PRX gene. This alteration results from a G to A substitution at nucleotide position 3271, causing the alanine (A) at amino acid position 1091 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV003418037	SCV004143756	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PRX: PM2, BP4
Breakthrough Genomics, Breakthrough Genomics	RCV003418037	SCV005194621	uncertain significance	not provided		criteria provided, single submitter	not provided
Genesis Genome Database	RCV000857050	SCV000999621	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research