Submissions for variant NM_032634.4(PIGO):c.1810dup (p.Arg604fs)

dbSNP: rs774508288

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790806	SCV000339436	pathogenic	not provided	2016-02-22	criteria provided, single submitter	clinical testing
Invitae	RCV000358032	SCV000652679	pathogenic	Hyperphosphatasia with intellectual disability syndrome 2	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg604Profs*40) 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 (rs774508288, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with a PIGO-related disorder (PMID: 28545593). ClinVar contains an entry for this variant (Variation ID: 286126). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000611172	SCV000731989	likely pathogenic	Hyperphosphatasia-intellectual disability syndrome	2017-09-29	criteria provided, single submitter	clinical testing	The p.Arg604ProfsX40 variant in PIGO has not been previously reported in indivi duals with hyperphosphatasia with intellectual disability syndrome, but has been reported in ClinVar (Variation ID#286126). It has been identified in 0.033% (42 /126,578) European chromosomes by the Genome Aggregation Database (http://gnomad .broadinstitute.org; dbSNP rs774508288). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rece ssive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 604 and leads to a premature termination codon 40 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the PIGO gene has been associated with hyperphosphatasia with intellectual di sability syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg604ProfsX40 variant is likely pat hogenic for hyperphosphatasia with intellectual disability syndrome in an autoso mal recessive manner based on a predicted variant effect. ACMG/AMP Criteria appl ied: PVS1; PM2 (Richards 2015).
GeneDx	RCV000790806	SCV001167922	likely pathogenic	not provided	2023-09-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30609409, 22683086, 34313030, 24417746, 31980526, 31589614, 28545593, 31440721)
MGZ Medical Genetics Center	RCV000358032	SCV002580833	pathogenic	Hyperphosphatasia with intellectual disability syndrome 2	2021-12-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000358032	SCV002799195	pathogenic	Hyperphosphatasia with intellectual disability syndrome 2	2022-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002521948	SCV003653330	pathogenic	Inborn genetic diseases	2022-01-05	criteria provided, single submitter	clinical testing	The c.1810dupC (p.R604Pfs*40) alteration, located in exon 7 (coding exon 6) of the PIGO gene, consists of a duplication of C at position 1810, causing a translational frameshift with a predicted alternate stop codon after 40 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the dupC allele has an overall frequency of 0.02% (44/282630) total alleles studied. The highest observed frequency was 0.03% (42/129018) of European (non-Finnish) alleles. This alteration has been reported compound heterozygous in a patient with facial dysmorphism, psychomotor disability, epilepsy, palmoplantar keratoderma, hyperphosphatasemia, and platelet dysfunction without a clinical bleeding phenotype (Morren, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000358032	SCV003835516	pathogenic	Hyperphosphatasia with intellectual disability syndrome 2	2022-09-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000358032	SCV003934050	pathogenic	Hyperphosphatasia with intellectual disability syndrome 2	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: PIGO c.1810dupC (p.Arg604ProfsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 251232 control chromosomes (gnomAD). c.1810dupC has been reported in the literature in an individual affected with PIGO deficiency (example: Morren_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28545593). Eight 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 pathogenic.