rs139073416

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_017837.4(PIGV):c.1022C>A(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A341V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

PIGV
NM_017837.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 5.69

Variant links:

Genes affected

PIGV (HGNC:26031): (phosphatidylinositol glycan anchor biosynthesis class V) This gene encodes a mannosyltransferase enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is a complex glycolipid that functions as a membrane anchor for many proteins and plays a role in multiple cellular processes including protein sorting and signal transduction. The encoded protein is localized to the endoplasmic reticulum and transfers the second mannose to the GPI backbone. Mutations in this gene are associated with hyperphosphatasia cognitive disability syndrome. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Feb 2011]

PIGV links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity PIGV_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_017837.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-26795056-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1287.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

PP5

Variant 1-26795056-C-A is Pathogenic according to our data. Variant chr1-26795056-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-26795056-C-A is described in Lovd as [Likely_pathogenic]. Variant chr1-26795056-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGV	NM_017837.4 link	c.1022C>A	p.Ala341Glu	missense_variant	Exon 3 of 4	ENST00000674202.1	NP_060307.2	Q9NUD9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGV	ENST00000674202.1 link	c.1022C>A	p.Ala341Glu	missense_variant	Exon 3 of 4		NM_017837.4	ENSP00000501479.1		Q9NUD9

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251478

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000138

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 1

Pathogenic:9

Dec 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.83 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001284).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 20802478, 24129430).A different missense change at the same codon (p.Ala341Val) has been reported to be associated with PIGV related disorder (ClinVar ID: VCV000001287). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 11, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 27, 2023

Department of Clinical Genetics, Medical University of Lodz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3_strong, PM2, PM5_supporting -

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 11, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PM3,PM5,PM2_SUP,PP3 -

not provided

Pathogenic:3

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PIGV protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PIGV function (PMID: 20802478). For these reasons, this variant has been classified as Pathogenic. -

Jan 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Aug 08, 2013

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PIGV-related disorder

Pathogenic:1

Aug 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PIGV c.1022C>A variant is predicted to result in the amino acid substitution p.Ala341Glu. This variant in the homozygous and compound heterozygous conditions were reported to be pathogenic for autosomal recessive hyperphosphatasia with intellectual disability syndrome, and hyperphosphatasia with seizures and neurologic deficit (Krawitz et al. 2010. PubMed ID: 20802478; Evers et al. 2017. PubMed ID: 28688840; Horn et al. 2011. PubMed ID: 21739589; Thompson et al. 2012. PubMed ID: 22315194). A different variant affecting the same amino acid residue (p.Ala341Val) was reported to be pathogenic (Thompson et al. 2012. PubMed ID: 22315194). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Hyperphosphatasia-intellectual disability syndrome

Pathogenic:1

Jan 27, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

.;T

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.2

N;N

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.96

D;D

Vest4

0.85

MVP

0.96

MPC

0.66

ClinPred

0.46

GERP RS

4.1

Varity_R

0.64

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over