rs201322234
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM2PM5PP2PP5_Very_StrongBP4
The NM_001244710.2(GFPT1):c.331C>T(p.Arg111Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R111H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001244710.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GFPT1 | NM_001244710.2 | c.331C>T | p.Arg111Cys | missense_variant | 4/20 | ENST00000357308.9 | |
GFPT1 | NM_002056.4 | c.331C>T | p.Arg111Cys | missense_variant | 4/19 | ||
GFPT1 | XM_017003801.2 | c.406C>T | p.Arg136Cys | missense_variant | 4/20 | ||
GFPT1 | XM_017003802.3 | c.406C>T | p.Arg136Cys | missense_variant | 4/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFPT1 | ENST00000357308.9 | c.331C>T | p.Arg111Cys | missense_variant | 4/20 | 5 | NM_001244710.2 |
Frequencies
GnomAD3 genomes ? AF: 0.000296 AC: 45AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251416Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135888
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461738Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727168
GnomAD4 genome ? AF: 0.000296 AC: 45AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32AN XY: 74424
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 12 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 11, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 15, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GFPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 29735). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21310273, 23794683, 28712002). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs201322234, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 111 of the GFPT1 protein (p.Arg111Cys). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 02, 2018 | The GFPT1 c.331C>T (p.Arg111Cys) missense variant has been reported in two studies and identified in nine individuals with congenital myasthenic syndrome, including in six homozygotes and in three compound heterozygotes, from four unrelated families (Senderek et al. 2011; Bauche et al. 2017). Segregation data from the families was consistent with autosomal recessive inheritance. The p.Arg111Cys variant was absent from at least 240 controls but is reported at a frequency of 0.000566 in the Latino population of the Genome Aggregation Database. In addition, Bauche et al. (2017) identified four unrelated affected individuals that carried a different amino acid change at the same residue (p.Arg111His) in a compound heterozygous state, suggesting that the Arg111 codon may be a mutational hot spot. Based on the evidence, the p.Arg111Cys variant is classified as likely pathogenic for congenital myasthenic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.62). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029735). A different missense change at the same codon (p.Arg111His) has been reported to be associated with GFPT1 related disorder (ClinVar ID: VCV001073321). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at