NM_176787.5(PIGN):c.654T>G (p.His218Gln) AND Multiple congenital anomalies-hypotonia-seizures syndrome 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 28, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000649307.4

Allele description [Variation Report for NM_176787.5(PIGN):c.654T>G (p.His218Gln)]

NM_176787.5(PIGN):c.654T>G (p.His218Gln)

Gene:
PIGN:phosphatidylinositol glycan anchor biosynthesis class N [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q21.33
Genomic location:
Preferred name:
NM_176787.5(PIGN):c.654T>G (p.His218Gln)
HGVS:
  • NC_000018.10:g.62148234A>C
  • NG_033144.1:g.43823T>G
  • NM_012327.6:c.654T>G
  • NM_176787.5:c.654T>GMANE SELECT
  • NP_036459.1:p.His218Gln
  • NP_789744.1:p.His218Gln
  • NC_000018.9:g.59815467A>C
  • NM_176787.4:c.654T>G
Protein change:
H218Q
Links:
dbSNP: rs1035743375
NCBI 1000 Genomes Browser:
rs1035743375
Molecular consequence:
  • NM_012327.6:c.654T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_176787.5:c.654T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1)
Synonyms:
GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 3; PIGN-CDG; Congenital disorder of glycosylation due to PIGN deficiency
Identifiers:
MONDO: MONDO:0013563; MedGen: C3279775; Orphanet: 280633; OMIM: 614080

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000771134Invitaecriteria provided, single submitter
Uncertain significance
(Oct 28, 2019)
germlineclinical testing

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

SCV001554481Equipe Genetique des Anomalies du Developpement, Université de Bourgognecriteria provided, single submitter
Likely pathogenicpaternalclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedpaternalyesnot providednot providednot providednot providednot 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):240-242.

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 Invitae, SCV000771134.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces histidine with glutamine at codon 218 of the PIGN protein (p.His218Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PIGN-related disease. ClinVar contains an entry for this variant (Variation ID: 539554). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5

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

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001554481.1

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

Last Updated: Sep 23, 2021

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