Submissions for variant NM_004855.5(PIGB):c.847-10A>G

dbSNP: rs779296101

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics and Molecular Pathology, SA Pathology	RCV000850267	SCV002557027	pathogenic	Developmental and epileptic encephalopathy, 80	2021-11-03	criteria provided, single submitter	clinical testing	The PIGB c.847-10A>G variant is classified as PATHOGENIC (PS4, PVS1) The PIGB c.847-10A>G is a single nucleotide change located in intron 7 of the gene. Studies have demonstrated that this variant introduces a new acceptor site and results in no wild-type mRNA being expressed (PMID:31256876). This variant has been previously reported in a homozygous state in affected individuals from multiple families with glycosylphosphatidylinositol deficiency (PMID:31256876) (PS4). This variant is in dbSNP (rs779296101) but is rare in population databases (gnomAD 1/152128 alleles). This variant has been reported in ClinVar as pathogenic for developmental and epileptic encephalopathy 80 by another diagnostic laboratory (Variation ID:689519). It is also reported as damaging in the disease database HGMD (CS1915182).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002538350	SCV003474094	pathogenic	not provided	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the PIGB gene. It does not directly change the encoded amino acid sequence of the PIGB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs779296101, gnomAD 0.05%). This variant has been observed in individual(s) with PIGB-related conditions (PMID: 31256876). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 689519). Studies have shown that this variant alters PIGB gene expression (PMID: 31256876, 32123317). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 31256876). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000850267	SCV004041364	pathogenic	Developmental and epileptic encephalopathy, 80	2023-07-27	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000850267	SCV004046878	pathogenic	Developmental and epileptic encephalopathy, 80	2023-10-23	criteria provided, single submitter	clinical testing	This homozygous intronic variant is identified in a 3 month male with poor feeding, coarse face, who later developed GDD hypertrichosis and raised alkaline phosphatase. Microanalysis: normal. Sibling died with a similar phenotype. This change present in gnomAD database with an allele frequency of 0.0065% [PM2]. To our knowledge there are no homozygotes in gnomAd database for this variant. Insilico prediction [SpliceAI, dbscSNV] predicts a splice-altering nature of this variant [PP3]. A clinvar entry [Variation ID: 689519] for this variant is available with a “Pathogenic” interpretation by multiple submitter. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic"
OMIM	RCV000850267	SCV000992439	pathogenic	Developmental and epileptic encephalopathy, 80	2020-10-20	no assertion criteria provided	literature only