ClinVar Miner

Submissions for variant NM_001244710.2(GFPT1):c.44C>T (p.Thr15Met)

gnomAD frequency: 0.00002  dbSNP: rs751097758
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001378308 SCV001575853 pathogenic Congenital myasthenic syndrome 12 2024-12-31 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 15 of the GFPT1 protein (p.Thr15Met). This variant is present in population databases (rs751097758, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21310273, 23569079, 23794683, 28712002; internal data). 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: 1067128). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Thr15 amino acid residue in GFPT1. Other variant(s) that disrupt this residue have been observed in individuals with GFPT1-related conditions (PMID: 21310273), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003331142 SCV004039062 pathogenic Congenital myasthenic syndrome 2023-08-11 criteria provided, single submitter clinical testing Variant summary: GFPT1 c.44C>T (p.Thr15Met) results in a non-conservative amino acid change located in the glutamine amidotransferase type 2 domain (IPR017932) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251206 control chromosomes (gnomAD). c.44C>T has been reported in the literature in multiple bi-allelic individuals affected with Congenital Myasthenic Syndrome (examples: Senderek_2011, Zoltowska_2013, Selcen_2013, Bauche_2017, Gonzalez-Quereda_2020, Zhao_2021, An_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36188410, 28712002, 32403337, 23794683, 21310273, 33756069, 23569079). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001378308 SCV005657221 pathogenic Congenital myasthenic syndrome 12 2024-04-15 criteria provided, single submitter clinical testing

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