Submissions for variant NM_004204.5(PIGQ):c.942+1G>A

gnomAD frequency: 0.00006  dbSNP: rs200661329

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000518843	SCV000621855	likely pathogenic	not provided	2023-07-19	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32746448, 32588908)
Invitae	RCV000537621	SCV000626122	pathogenic	Epilepsy	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the PIGQ gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIGQ are known to be pathogenic (PMID: 24463883, 25558065). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with PIGQ-related conditions (PMID: 32588908). 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: 453003). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Undiagnosed Diseases Network, NIH	RCV000787940	SCV000926961	likely pathogenic	PIGQ-related disorder	2018-05-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002527652	SCV003702723	pathogenic	Inborn genetic diseases	2021-07-27	criteria provided, single submitter	clinical testing	The c.942+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 4 (coding exon 3) of the PIGQ gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.01% (9/158484) total alleles studied. The highest observed frequency was 0.02% (6/25454) of Latino alleles. The c.942+1G>A alteration has been described in trans with a second disease-causing alteration in a patient with seizures, developmental delay, truncal hypotonia, abnormal movements, feeding issues, facial dysmorphism, and anomalies of the skeletal, ophthalmological, cardiac, gastrointestinal, and genitourinary systems (Johnstone, 2020). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290116	SCV003922923	likely pathogenic	Developmental and epileptic encephalopathy, 77	2023-03-23	criteria provided, single submitter	clinical testing	Variant summary: PIGQ c.942+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant allele was found at a frequency of 5.7e-05 in 158484 control chromosomes (gnomAD). One in silico tool predicts damaging effect on splicing for this variant (TraP Score: 0.9). However, these predictions have not been tested experimentally. c.942+1G>A has been reported in the literature in individuals affected with PIGQ related conditions (example: Johnstone_2020 and Burstein_PR_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV001290116	SCV001478257	pathogenic	Developmental and epileptic encephalopathy, 77	2021-01-26	no assertion criteria provided	literature only