rs139073416
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_017837.4(PIGV):โc.1022C>Aโ(p.Ala341Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A341V) has been classified as Pathogenic.
Frequency
Consequence
NM_017837.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGV | NM_017837.4 | c.1022C>A | p.Ala341Glu | missense_variant | 3/4 | ENST00000674202.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGV | ENST00000674202.1 | c.1022C>A | p.Ala341Glu | missense_variant | 3/4 | NM_017837.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000115 AC: 29AN: 251478Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135914
GnomAD4 exome AF: 0.0000855 AC: 125AN: 1461884Hom.: 0 Cov.: 34 AF XY: 0.0000894 AC XY: 65AN XY: 727242
GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74348
ClinVar
Submissions by phenotype
Hyperphosphatasia with intellectual disability syndrome 1 Pathogenic:8
Pathogenic, criteria provided, single submitter | literature only | Department of Clinical Genetics, Medical University of Lodz | Jul 27, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 11, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 27, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 11, 2017 | This variant was identified comp-het. with Chr1: 27121132; NM_017837.3: c.607C>T; p.(Arg203Cys) - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Sep 15, 2023 | PS3, PM3_strong, PM2, PM5_supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 30, 2021 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 13, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | 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. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2013 | - - |
Hyperphosphatasia-intellectual disability syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 27, 2017 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at