Submissions for variant NM_017837.4(PIGV):c.1022C>A (p.Ala341Glu)

gnomAD frequency: 0.00014  dbSNP: rs139073416

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190698	SCV000244139	pathogenic	Inborn genetic diseases	2013-08-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000396582	SCV000329466	pathogenic	not provided	2022-01-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Krawitz et al., 2010; Murakami et al., 2012); This variant is associated with the following publications: (PMID: 20802478, 22228761, 24129430, 22315194, 21739589, 28688840, 31980526, 33402532, 31589614, 33144682)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000613584	SCV000731428	likely pathogenic	Hyperphosphatasia-intellectual disability syndrome	2017-01-27	criteria provided, single submitter	clinical testing	The p.Ala341Glu variant in PIGV has been identified in at least 10 individuals w ith hyperphosphatasia-intellectual disability syndrome (HPMR; Krawitz 2010, Horn 2011, Murakami 2012, Horn 2014), all of whom were either homozygous or compound heterozygous. This variant segregated with disease in at least 2 affected famil y members. It was also identified in 0.02% (30/126708) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs139073416). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . Furthermore, in vitro functional studies provide some evidence that the p.Ala3 41Glu variant may impact protein function (Murakami 2012). In summary, although additional studies are required to fully establish its clinical significance, th e p.Ala341Glu variant is likely pathogenic for hyperphosphatasia-intellectual di sability syndrome inherited in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP1, PS3_Supporting (Richards 2015).
Mayo Clinic Laboratories, Mayo Clinic	RCV000001347	SCV000782624	pathogenic	Hyperphosphatasia with intellectual disability syndrome 1	2017-01-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000001347	SCV000893983	pathogenic	Hyperphosphatasia with intellectual disability syndrome 1	2021-12-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001347	SCV000915408	pathogenic	Hyperphosphatasia with intellectual disability syndrome 1	2019-01-11	criteria provided, single submitter	clinical testing	Across a selection of the literature, the PIGV c.1022C>A (p.Ala341Glu) missense variant was observed in a total of 17 individuals with hyperphosphatasia with mental retardation syndrome, including in nine in a homozygous state (three of whom were related) and in eight in a compound heterozygous state (two of whom were related). The p.Ala341Glu variant was absent from 350 controls and 4,000 exomes (Krawitz et al. 2010; Horn et al. 2011; Thompson et al. 2012; Horn et al. 2014). The variant is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Functional studies by Krawitz et al. (2010) showed that PIGV-deficient CHO cells transfected with wild type PIGV were able to restore surface expression of marker proteins, but that cells carrying the p.Ala341Glu variant were unable to restore expression. Murakami et al. (2012) produced similar results, and also demonstrated that expression of the p.Ala341Glu variant protein was drastically reduced as compared to wild type. The highest allele frequency reported in the Exome Sequencing Project is 0.00035 in the European American population. Based on the collective evidence, the p.Ala341Glu variant is classified as pathogenic for hyperphosphatasia with intellectual disability syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000001347	SCV000999270	pathogenic	Hyperphosphatasia with intellectual disability syndrome 1		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000396582	SCV001447578	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV000396582	SCV001586242	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 341 of the PIGV protein (p.Ala341Glu). This variant is present in population databases (rs139073416, gnomAD 0.02%). This missense change has been observed in individuals with hyperphosphatasia mental retardation syndrome (PMID: 20802478, 28688840). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1284). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIGV protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIGV function (PMID: 20802478). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000001347	SCV002026276	pathogenic	Hyperphosphatasia with intellectual disability syndrome 1	2017-08-11	criteria provided, single submitter	clinical testing	This variant was identified comp-het. with Chr1: 27121132; NM_017837.3: c.607C>T; p.(Arg203Cys)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000001347	SCV004099143	pathogenic	Hyperphosphatasia with intellectual disability syndrome 1	2023-09-15	criteria provided, single submitter	clinical testing	PS3, PM3_strong, PM2, PM5_supporting
Department of Clinical Genetics, Medical University of Lodz	RCV000001347	SCV004801723	pathogenic	Hyperphosphatasia with intellectual disability syndrome 1	2023-07-27	criteria provided, single submitter	literature only
OMIM	RCV000001347	SCV000021497	pathogenic	Hyperphosphatasia with intellectual disability syndrome 1	2012-03-01	no assertion criteria provided	literature only