Submissions for variant NM_004278.4(PIGL):c.336-2A>G

gnomAD frequency: 0.00007  dbSNP: rs369230457

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779203	SCV000915743	uncertain significance	CHIME syndrome	2018-10-15	criteria provided, single submitter	clinical testing	This variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of uncertain significance but suspicious for pathogenicity for this disease.
GeneDx	RCV001561717	SCV001784367	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Reported in an individual in published literature with features of PIGL-related disorder (Pagnamenta et al., 2017); This variant is associated with the following publications: (PMID: 28327575)
Invitae	RCV001561717	SCV004328373	pathogenic	not provided	2023-09-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the PIGL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs369230457, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with clinical features of CHIME syndrome (PMID: 28327575). 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: 632268). Studies have shown that disruption of this splice site results in skipping of exon 3 and introduces a premature termination codon (PMID: 28327575). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.