Submissions for variant NM_032634.4(PIGO):c.589_590del (p.Pro197fs)

dbSNP: rs763591247

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779580	SCV000916259	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2018-10-21	criteria provided, single submitter	clinical testing	This variant results in a frameshift and is predicted to result in premature termination of the protein. 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, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
GeneDx	RCV001009084	SCV001168894	likely pathogenic	not provided	2018-10-09	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the PIGO gene. The c.589_590delCC variant is not observed in large population cohorts (Lek et al., 2016). The c.589_590delCC variant causes a frameshift starting with codon Proline 197, changes this amino acid to an Isoleucine residue and creates a premature Stop codon at position 26 of the new reading frame, denoted p.Pro197IlefsX26. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000779580	SCV002246691	pathogenic	Hyperphosphatasia with intellectual disability syndrome 2	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro197Ilefs*26) in the PIGO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIGO are known to be pathogenic (PMID: 22683086, 24417746). This variant is present in population databases (rs763591247, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PIGO-related conditions. ClinVar contains an entry for this variant (Variation ID: 632540). For these reasons, this variant has been classified as Pathogenic.