chr9-36227397-C-G
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PM5PP2PP5_Very_Strong
The NM_001128227.3(GNE):c.1225G>C(p.Asp409His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D409E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001128227.3 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.1225G>C | p.Asp409His | missense_variant | Exon 7 of 12 | 1 | NM_001128227.3 | ENSP00000379839.3 | ||
GNE | ENST00000642385.2 | c.1132G>C | p.Asp378His | missense_variant | Exon 7 of 12 | NM_005476.7 | ENSP00000494141.2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460436Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726622 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
GNE myopathy Pathogenic:1
Variant summary: GNE c.1225G>C (p.Asp409His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes. c.1225G>C has been reported in the literature in at-least two individuals affected with Hereditary Muscle Disorders and GNE-related myopathy (Chen_2019, Khadilkar_2021,2022, Lv_2022). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1225G>T, p.Asp409Tyr), supporting the critical relevance of codon 409 to GNE protein function. 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: 30390020, 35723113, 33197058, 35138478). ClinVar contains an entry for this variant (Variation ID: 1324492). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at