ClinVar Miner

Submissions for variant NM_002056.4(GFPT1):c.331C>T (p.Arg111Cys) (rs201322234)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000022587 SCV000915920 likely pathogenic Congenital myasthenic syndrome 12 2018-03-02 criteria provided, single submitter clinical testing 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.
Invitae RCV000022587 SCV000964958 pathogenic Congenital myasthenic syndrome 12 2019-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 111 of the GFPT1 protein (p.Arg111Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201322234, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another GFPT1 variant in several individuals affected with congenital myasthenic syndrome (PMID: 21310273, 23794683, 28712002). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been observed to segregate with disease in affected families (PMID: 21310273, 28712002). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 29735). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090973 SCV001246776 likely pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
OMIM RCV000022587 SCV000043876 pathogenic Congenital myasthenic syndrome 12 2011-02-11 no assertion criteria provided literature only

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