ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.769+4A>G

dbSNP: rs886063926
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000332020 SCV000480104 uncertain significance GNE myopathy 2017-04-27 criteria provided, single submitter clinical testing The GNE c.769+4A>G variant is a splice region variant that has been found in a compound heterozygous state in at least two individuals with GNE-related myopathy (Nishino et al. 2002; Fischer et al. 2013). Control data are unavailable for this variant, which is not found in the 1000 Genomes Project, Exome Sequencing Project or Exome Aggregation Consortium despite being located in a region of good sequencing coverage. The variant is thus presumed to be rare. Nishino et al. (2002) reported that the c.769+4A>G variant resulted in virtually complete skipping of exon 4 when cDNA was analyzed. The evidence for this variant is limited. The c.769+4A>G variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for GNE-related myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina RCV000386564 SCV000480105 uncertain significance Sialuria 2017-04-27 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003766110 SCV004569764 pathogenic GNE myopathy; Sialuria 2023-06-06 criteria provided, single submitter clinical testing This variant has been observed in individuals with clinical features of autosomal recessive distal myopathy (PMID: 12473753, 24027297; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the GNE gene. It does not directly change the encoded amino acid sequence of the GNE protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is also known as IVS4+4A>G and c.769+4A>G. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 12473753). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 366844).

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