ClinVar Miner

Submissions for variant NM_032634.4(PIGO):c.1810dup (p.Arg604fs) (rs774508288)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790806 SCV000339436 pathogenic not provided 2016-02-22 criteria provided, single submitter clinical testing
Invitae RCV000358032 SCV000652679 pathogenic Hyperphosphatasia with mental retardation syndrome 2 2018-11-30 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. This variant is present in population databases (rs774508288, ExAC 0.02%). This variant has been reported in an individual affected with a PIGO-related disorder (PMID: 28545593). ClinVar contains an entry for this variant (Variation ID: 286126). Loss-of-function variants in PIGO are known to be pathogenic (PMID: 24417746, 22683086). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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; 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).

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