Submissions for variant NM_006096.3(NDRG1):c.31G>A (p.Ala11Thr) (rs145871479)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083085	SCV000261903	likely benign	Charcot-Marie-Tooth disease type 4	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000236080	SCV000292635	uncertain significance	not specified	2017-09-20	criteria provided, single submitter	clinical testing	The A11T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The A11T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved through mammals. However, in silico analysis predicts this variant likely does not alter the protein structure/function. Additionally missense mutations have not been reported in the NDRG1 gene in association with neuropathy (Stenson et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Athena Diagnostics Inc	RCV000710163	SCV000614152	likely benign	not provided	2019-11-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000710163	SCV000884217	uncertain significance	not provided	2017-06-14	criteria provided, single submitter	clinical testing	The p.Ala11Thr variant (rs145871479) has not been reported in the medical literature; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 220934). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.11% (identified in 309 out of 277,200 chromosomes, including 1 homozygote). The alanine at codon 111 is only moderately conserved considering 15 species (Alamut software v2.9), and computational analyses suggest this variant does not have a significant effect on NDRG1 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Ala11Thr variant cannot be determined with certainty.
Illumina Clinical Services Laboratory,Illumina	RCV001162095	SCV001324030	uncertain significance	Charcot-Marie-Tooth disease, type 4D	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.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001173729	SCV001336843	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001083085	SCV001456524	likely benign	Charcot-Marie-Tooth disease type 4	2019-12-27	no assertion criteria provided	clinical testing