NM_001128227.3:c.1900C>T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2PP5
The NM_001128227.3(GNE):c.1900C>T(p.Leu634Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001128227.3 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.1900C>T | p.Leu634Phe | missense_variant | Exon 10 of 12 | 1 | NM_001128227.3 | ENSP00000379839.3 | ||
GNE | ENST00000642385.2 | c.1807C>T | p.Leu603Phe | missense_variant | Exon 10 of 12 | NM_005476.7 | ENSP00000494141.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000795 AC: 2AN: 251450 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461700Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727172 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74358 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
GNE myopathy Pathogenic:2Uncertain:2
Variant summary: GNE c.1900C>T (p.Leu634Phe) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 8e-06 in 251450 control chromosomes. c.1900C>T has been reported in the literature in individuals affected with Inclusion Body Myopathy 2 (Mori-Yoshimura_2012, Cho_2014, Paul_2020). 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. The following publications have been ascertained in the context of this evaluation (PMID: 22507750, 24027297, 32505938). ClinVar contains an entry for this variant (Variation ID: 283229). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not provided Uncertain:2
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Sialuria;C1853926:GNE myopathy Pathogenic:1
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 634 of the GNE protein (p.Leu634Phe). This variant is present in population databases (rs372732220, gnomAD 0.002%). This missense change has been observed in individual(s) with GNE-related myopathy (PMID: 22507750, 24027297, 32505938). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 283229). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at