Submissions for variant NM_001244710.2(GFPT1):c.*22C>A

dbSNP: rs199678034

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844698	SCV000245615	uncertain significance	not specified	2019-02-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.*22C>A variant in GFPT1 has been reported in 8 individuals with features of limb-girdle myasthenic syndrome (Senderek 2011, Selcen 2013, Bauche 2017, Natera-de Benito 2017). All of these individuals carried second variants in the GFPT1 gene; however, in only 3 of these probands were the variants confirmed to be in trans and have sufficient evidence to be classified as likely pathogenic or pathogenic(Senderek 2011, Selcen 2013). Furthermore, the variant segregated with disease in 7 affected individuals from 5 families (Senderek 2011, Selcen 2013). It has also been identified in 0.23% (297/128550) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has been reported with conflicting interpretations in ClinVar (Variant ID 208585). This variant is located in the 3' untranslated region. In vitro functional studies provide some evidence that the c.*22C>A variant may lead to reduced GFPT1 protein levels by influencing miRNA binding and thereby protein translation (Senderek 2011, Muller 2012, Dusl 2015). However, the assay may not accurately represent the in vivo environment and the reduction in protein levels may not be sufficient for disease. While the biallelic occurrences, segregation in affected individuals, and in vitro functional studies support a disease-causing role, given the relatively high frequency of this variant in the general population, there is some concern that the biallelic occurrences may have been seen by chance (therefore the PM3 evidence was downgraded) or that the variant may be in linkage disequilibrium with another pathogenic variant in the families described (therefore PP1 evidence was downgraded). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.*22C>A variant is uncertain. ACMG/AMP guidelines applied: BS1_Supporting, PM3_Supporting, PP1_Moderate, PS3_Supporting.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514285	SCV000610322	uncertain significance	not provided	2017-03-31	criteria provided, single submitter	clinical testing
Invitae	RCV000190590	SCV000652532	pathogenic	Congenital myasthenic syndrome 12	2024-01-29	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the GFPT1 gene. It does not change the encoded amino acid sequence of the GFPT1 protein. This variant is present in population databases (rs199678034, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21310273, 23488891, 23794683). 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: 208585). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GFPT1 function (PMID: 21310273, 25765662). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000190590	SCV000915919	uncertain significance	Congenital myasthenic syndrome 12	2018-09-21	criteria provided, single submitter	clinical testing	The GFPT1 c.*22C>A variant has been reported in at least three studies in which it is found in a compound heterozygous state in eight unrelated probands from a total of 13 affected individuals, and in a heterozygous state in four asymptomatic relatives (Senderek et al. 2011; Maselli et al. 2013; Selcen et al. 2013). The c.*22C>A variant was absent from 635 control subjects (Senderek et al. 2011) and is reported at a frequency of 0.002462 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in myoblast cell lines derived from patients carrying the c.*22C>A variant showed reduction in GFPT1 protein levels, while the level of mRNA was similar to wild type GFPT1 (Dusl et al. 2015). In silico analysis and an in vitro reporter gene assay indicated that the c.*22C>A variant leads to a gain of putative binding sites for a microRNA, which was shown to mediate the reduction in GFPT1 protein expression (Dusl et al. 2015). Despite the available clinical data, the frequency of the variant in the public databases is too high to be causative of disease based on the known disease prevalence and penetrance. Therefore taking into account the conflicting evidence, the c.*22C>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for the autosomal recessive form of congenital myasthenic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000190590	SCV001522436	likely pathogenic	Congenital myasthenic syndrome 12	2020-04-12	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000514285	SCV002526633	likely pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect with the formation of a microRNA binding site resulting in reduced protein expression (Dusl et al., 2015); This variant is associated with the following publications: (PMID: 21310273, 26501342, 23488891, 27472506, 21975507, 26721333, 28754144, 29054425, 31047772, 23794683, 34978387, 36188410, 28712002, 25765662)
MGZ Medical Genetics Center	RCV000190590	SCV002581388	likely pathogenic	Congenital myasthenic syndrome 12	2022-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469055	SCV002766156	likely pathogenic	Congenital myasthenic syndrome	2022-11-15	criteria provided, single submitter	clinical testing	Variant summary: GFPT1 c.*22C>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0013 in 249944 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in GFPT1 causing Congenital Myasthenic Syndrome phenotype (0.0005), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. However, c.*22C>A has also been reported in the literature in the compound heterozygous state in as many as 17 affected individuals from 8 different families with Congenital Myasthenic Syndrome, including multiple cases where the variant segregates with disease (e.g. Senderek_2011, Selcen_2013, Maselli_2014), suggesting that the variant is likely to be associated with disease. At least two publications report that GFPT1 protein, but not mRNA levels, are reduced in muscle cells from patients harboring the c.*22C>A variant compared to healthy control individuals (e.g. Senderek_2011, Dusl_2015) and a similar relationship was observed in myoblasts expressing the variant compared to wild-type (Dusl_2015). One of these publications also provided evidence to support that the variant may allow for binding of a microRNA, that is expressed in myoblasts, myotubes and skeletal muscle, which may cause the reduction in GFPT1 protein expression by repressing translation (Dusl_2015). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Three classified the variant as VUS, three classified it as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000514285	SCV002035305	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000514285	SCV002036779	likely pathogenic	not provided		no assertion criteria provided	clinical testing