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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:
3

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000479866Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV000652698Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely benign
(Dec 27, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001431201New York Genome Center - CSER-NYCKidSeq
criteria provided, single submitter

(NYGC Assertion Criteria 2020)
Uncertain significance
(May 7, 2020)
germlineclinical testing

Citation Link,

SCV004037344Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jan 24, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot provided2not providedclinical testing
Hispanic Americangermlineunknown1not providednot provided1not providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
2not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided
2germlineunknown1not providednot provided1not providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Hispanic American1not providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1DNA from products of conceptionvalidation1not providednot providednot provided

Last Updated: Sep 29, 2024