Submissions for variant NM_001244710.2(GFPT1):c.43A>G (p.Thr15Ala)

dbSNP: rs387906638

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700268	SCV005203706	uncertain significance	not specified	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: GFPT1 c.43A>G (p.Thr15Ala) 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 was absent in 251206 control chromosomes. c.43A>G has been reported in the literature in at least one compound heterozygous individual affected with Congenital Myasthenic Syndrome (Senderek_2011, Guergueltcheva_2012). These data do not allow any conclusion about variant significance. A different variant affecting the same codon has been classified as pathogenic by our lab (c.44C>T, p.Thr15Met), supporting the critical relevance of codon 15 to GFPT1 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >60% of normal glutamine-fructose-6-phosphate transaminase 1 activity in transfected cells (Senderek_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21975507, 21310273). ClinVar contains an entry for this variant (Variation ID: 29739). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022591	SCV005834318	uncertain significance	Congenital myasthenic syndrome 12	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 15 of the GFPT1 protein (p.Thr15Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21310273). ClinVar contains an entry for this variant (Variation ID: 29739). 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 tolerated. Experimental studies have shown that this missense change affects GFPT1 function (PMID: 21310273). This variant disrupts the p.Thr15 amino acid residue in GFPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21310273, 23569079, 23794683, 28712002; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM	RCV000022591	SCV000043880	pathogenic	Congenital myasthenic syndrome 12	2011-02-11	no assertion criteria provided	literature only