NM_032634.4(PIGO):c.3118G>A (p.Val1040Ile) AND Hyperphosphatasia with intellectual disability syndrome 2

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Dec 27, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001080844.22

Allele description [Variation Report for NM_032634.4(PIGO):c.3118G>A (p.Val1040Ile)]

NM_032634.4(PIGO):c.3118G>A (p.Val1040Ile)

Gene:

PIGO:phosphatidylinositol glycan anchor biosynthesis class O [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_032634.4(PIGO):c.3118G>A (p.Val1040Ile)

HGVS:

NC_000009.12:g.35089402C>T
NG_031990.1:g.12200G>A
NM_001201484.2:c.1867G>A
NM_032634.4:c.3118G>AMANE SELECT
NM_152850.4:c.1867G>A
NP_001188413.1:p.Val623Ile
NP_116023.2:p.Val1040Ile
NP_690577.2:p.Val623Ile
NC_000009.11:g.35089399C>T
NM_032634.3:c.3118G>A

Protein change:

V1040I

Links:

dbSNP: rs149439295

NCBI 1000 Genomes Browser:

rs149439295

Molecular consequence:

NM_001201484.2:c.1867G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032634.4:c.3118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_152850.4:c.1867G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hyperphosphatasia with intellectual disability syndrome 2 (HPMRS2)
Synonyms:: GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 6; HYPERPHOSPHATASIA WITH IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME 2
Identifiers:: MONDO: MONDO:0013882; MedGen: C3553637; Orphanet: 247262; OMIM: 614749

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Erysiphe aquilegiae (1)
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Prunus serrula (1)
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Concise Conserved Domain Links for Protein (Select 2462621560) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000479866	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV000652698	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Dec 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001431201	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (May 7, 2020)	germline	clinical testing	Citation Link,
SCV004037344	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 24, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	2	not provided	clinical testing
Hispanic American	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000479866.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000652698.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center - CSER-NYCKidSeq, SCV001431201.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center, SCV004037344.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Hispanic American	1	not provided	not provided	clinical testing	PubMed (1)

Description

Observed in trans with c.1723T>G

Description

The c.3118G>A variant in the PIGO gene is missense variant, which results in the substitution of a conserved valine residue at amino acid position 1040 for an isoleucine (NP_116023.2). This variant localizes to coding exon 10 of the PIGO gene (11 coding exons in total; NM_032634.4). In silico predictors for this variant are not consistent: It is predicted to be neutral to protein structure and/or function by PROVEAN, but is predicted to be damaging by SIFT. This variant was reported in Genome Aggregation Database (gnomAD) with an allelic frequency of 0.0325% (92 out of 282,864 alleles). This variant is reported in ClinVar with three submissions of conflicting interpretation of pathogenicity, with two laboratories classifying it as a variant of uncertain clinical significance and one variant classifying it as likely benign (Variation ID# 366753). To the best of our knowledge, this specific variant has not been reported in the literature. Given this evidence, the c.3118G>A, p.Val1040Ile variant in PIGO is considered a variant of uncertain clinical significance. Parental studies were not conducted at our laboratory, but this variant was reported to be paternally inherited at another laboratory in a separate pregnancy of same parents (2019).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	DNA from products of conception	validation		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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