ClinVar Miner

Submissions for variant NM_002056.4(GFPT1):c.*22C>A (rs199678034)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 va riant in GFPT1 has been reported in 8 individuals with features of limb-girdle m yasthenic syndrome (Senderek 2011, Selcen 2013, Bauche 2017, Natera-de Benito 20 17). 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 hav e sufficient evidence to be classified as likely pathogenic or pathogenic(Sender ek 2011, Selcen 2013). Furthermore, the variant segregated with disease in 7 aff ected individuals from 5 families (Senderek 2011, Selcen 2013). It has also been identified in 0.23% (297/128550) of European chromosomes by gnomAD (http://gnom, and has been reported with conflicting interpretations i n ClinVar (Variant ID 208585). This variant is located in the 3' untranslated re gion. In vitro functional studies provide some evidence that the c.*22C>A varian t may lead to reduced GFPT1 protein levels by influencing miRNA binding and ther eby protein translation (Senderek 2011, Muller 2012, Dusl 2015). However, the as say may not accurately represent the in vivo environment and the reduction in pr otein 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 ha ve been seen by chance (therefore the PM3 evidence was downgraded) or that the v ariant may be in linkage disequilibrium with another pathogenic variant in the f amilies described (therefore PP1 evidence was downgraded). In summary, while the re 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_Sup porting, 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 2018-12-06 criteria provided, single submitter clinical testing This sequence change falls in 3'UTR of the GFPT1 gene. It does not directly change the encoded amino acid sequence of the GFPT1 protein. This variant is present in population databases (rs199678034, ExAC 0.2%). This variant has been reported in the compound heterozygous state with other variants in GFPT1, and has been observed to segregate with disease, in many individuals and families affected with congenital myasthenic syndrome (CMS) (PMID: 21310273, 23794683, 23488891). ClinVar contains an entry for this variant (Variation ID: 208585). Experimental studies have shown that this 3'UTR change creates a microRNA binding site, which leads to reduced levels of GFPT1 protein expression (PMID: 25765662, 21310273). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,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.

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