Submissions for variant NM_001128227.3(GNE):c.79C>T (p.Arg27Ter)

dbSNP: rs794727279

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000598080	SCV000701243	uncertain significance	not provided	2018-03-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000383627	SCV000791364	uncertain significance	GNE myopathy	2017-05-09	criteria provided, single submitter	clinical testing
Invitae	RCV001060421	SCV001225108	pathogenic	GNE myopathy; Sialuria	2023-08-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg27*) in the GNE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNE are known to be pathogenic (PMID: 24027297). This variant is present in population databases (rs794727279, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 195244). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001167866	SCV001330411	uncertain significance	Sialuria	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	RCV000383627	SCV001330412	uncertain significance	GNE myopathy	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000383627	SCV003845165	likely pathogenic	GNE myopathy	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: GNE c.79C>T (p.Arg27X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant allele was found at a frequency of 4e-06 in 250480 control chromosomes (gnomAD). To our knowledge, no occurrence of c.79C>T in individuals affected with Inclusion Body Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and Pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.