NM_001244710.2:c.331C>T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_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 (★★).
Frequency
Consequence
NM_001244710.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GFPT1 | NM_001244710.2 | c.331C>T | p.Arg111Cys | missense_variant | Exon 4 of 20 | ENST00000357308.9 | NP_001231639.1 | |
GFPT1 | NM_002056.4 | c.331C>T | p.Arg111Cys | missense_variant | Exon 4 of 19 | NP_002047.2 | ||
GFPT1 | XM_017003801.2 | c.406C>T | p.Arg136Cys | missense_variant | Exon 4 of 20 | XP_016859290.1 | ||
GFPT1 | XM_017003802.3 | c.406C>T | p.Arg136Cys | missense_variant | Exon 4 of 19 | XP_016859291.1 |
Ensembl
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
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. -
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). This variant is present in population databases (rs201322234, gnomAD 0.06%). 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. ClinVar contains an entry for this variant (Variation ID: 29735). 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) indicates that this missense variant is not expected to disrupt GFPT1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
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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
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Congenital myasthenic syndrome Pathogenic:1
Variant summary: GFPT1 c.331C>T (p.Arg111Cys) results in a non-conservative amino acid change located in the glutamine amidotransferase type 2 domain (IPR017932) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251416 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GFPT1 causing Congenital Myasthenic Syndrome (0.00014 vs 0.0005), allowing no conclusion about variant significance. c.331C>T has been reported in the literature in the homozygous and compound heterozygous states in multiple individuals affected with Congenital Myasthenic Syndrome and segregated with disease in at least one family (e.g. Senderek_2011, Jiang_2022). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in HEK293 cells showed that this variant resulted in enzyme activity and subcellular localization that was similar to wildtype, however, it does not allow convincing conclusions about the variant effect (e.g. Senderek_2011). The following publications have been ascertained in the context of this evaluation (PMID: 34978387, 21310273). ClinVar contains an entry for this variant (Variation ID: 29735). Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at