Submissions for variant NM_005476.7(GNE):c.1412-4G>A

gnomAD frequency: 0.00009  dbSNP: rs146067766

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593407	SCV000706243	uncertain significance	not provided	2017-03-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001169666	SCV001332426	benign	Sialuria	2017-06-14	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001169667	SCV001332427	uncertain significance	GNE myopathy	2017-06-21	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001245184	SCV001418455	likely benign	GNE myopathy; Sialuria	2024-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553584	SCV001774487	uncertain significance	not specified	2021-07-20	criteria provided, single submitter	clinical testing	Variant summary: GNE c.1505-4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 251248 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (0.00014 vs 0.0011), allowing no conclusion about variant significance. c.1505-4G>A has been reported in the literature in at-least one Japanese individual with clinically and pathologically confirmed (prominent rimmed vacuoles in muscle biopsy) GNE myopathy (example, Nakamura_2017), as a non-informative genotype in another Japanese individual with GNE myopathy (example, Cho_2013) and has been cited by others (Celeste_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV000593407	SCV002043962	uncertain significance	not provided	2021-06-25	criteria provided, single submitter	clinical testing	In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27535533, 27919547, 24027297)
Revvity Omics, Revvity	RCV000593407	SCV003815083	uncertain significance	not provided	2021-04-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001169667	SCV002075644	uncertain significance	GNE myopathy	2020-02-11	no assertion criteria provided	clinical testing