VCV000402190.16 - ClinVar

NM_176787.5(PIGN):c.996T>G (p.Ile332Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_176787.5(PIGN):c.996T>G (p.Ile332Met)

Variation ID: 402190 Accession: VCV000402190.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q21.33 18: 62140447 (GRCh38) [ NCBI UCSC ] 18: 59807680 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 3, 2017	Sep 29, 2024	Jul 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_176787.5:c.996T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_789744.1:p.Ile332Met	missense
NM_012327.6:c.996T>G	NP_036459.1:p.Ile332Met	missense
NC_000018.10:g.62140447A>C
NC_000018.9:g.59807680A>C
NG_033144.1:g.51610T>G

... more HGVS ... less HGVS

Protein change

I332M

Other names

Canonical SPDI

NC_000018.10:62140446:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA16609540 dbSNP: rs1060499763 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PIGN		-	-	GRCh38 GRCh37	1214	1333

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Abnormal brain morphology	Likely pathogenic (1)	criteria provided, single submitter	-	RCV000454324.1
Multiple congenital anomalies-hypotonia-seizures syndrome 1	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 22, 2023	RCV000578405.19
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2024	RCV003314594.2
PIGN-related disorder	Uncertain significance (1)	criteria provided, single submitter	Sep 7, 2022	RCV003401442.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (-)	criteria provided, single submitter (Karaca et al. (Neuron 2015)) Method: research	Abnormal brain morphology (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000537969.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Publications: PubMed (1) PubMed: 26539891 Geographic origin: Turkey Tissue: Blood
Uncertain significance (Sep 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PIGN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119260.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The PIGN c.996T>G variant is predicted to result in the amino acid substitution p.Ile332Met. This variant has been reported in the homozygous and compound heterozygous … (more) The PIGN c.996T>G variant is predicted to result in the amino acid substitution p.Ile332Met. This variant has been reported in the homozygous and compound heterozygous state with a premature termination variant in two individuals with PIGN-related phenotypes (Karaca et al 2015. PubMed ID: 26539891, Sup Table 1A; Brunet T et al 2021. PubMed ID: 33619735, Supp Table). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (1 allele, http://gnomad.broadinstitute.org/variant/18-59807680-A-C), indicating it is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Pathogenic (Dec 06, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680336.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: female Tissue: blood
Pathogenic (Jul 10, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004014111.2 First in ClinVar: Jul 22, 2023 Last updated: Sep 29, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26539891, 33619735, 36322149, 35179230, 34540776) (less)
Likely pathogenic (Dec 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 1 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000746941.2 First in ClinVar: Feb 08, 2018 Last updated: Dec 11, 2022	Age: 10-19 years Sex: male Geographic origin: Iran
Likely pathogenic (May 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001496512.4 First in ClinVar: Mar 07, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 26539891‚ 33619735‚ 35179230 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 PIGN protein function. ClinVar contains an entry for this variant (Variation ID: 402190). This missense change has been observed in individual(s) with clinical features of PIGN congenital disorder of glycosylation (PMID: 26539891, 33619735, 35179230). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 332 of the PIGN protein (p.Ile332Met). (less)

Comment:

The PIGN c.996T>G variant is predicted to result in the amino acid substitution p.Ile332Met. This variant has been reported in the homozygous and compound heterozygous state with a premature termination variant in two individuals with PIGN-related phenotypes (Karaca et al 2015. PubMed ID: 26539891, Sup Table 1A; Brunet T et al 2021. PubMed ID: 33619735, Supp Table). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (1 allele, http://gnomad.broadinstitute.org/variant/18-59807680-A-C), indicating it is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26539891, 33619735, 36322149, 35179230, 34540776)

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 PIGN protein function. ClinVar contains an entry for this variant (Variation ID: 402190). This missense change has been observed in individual(s) with clinical features of PIGN congenital disorder of glycosylation (PMID: 26539891, 33619735, 35179230). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 332 of the PIGN protein (p.Ile332Met).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PIGN encephalopathy: Characterizing the epileptology.	Bayat A	Epilepsia	2022	PMID: 35179230
De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.	Brunet T	Clinical genetics	2021	PMID: 33619735
Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.	Karaca E	Neuron	2015	PMID: 26539891

Text-mined citations for rs1060499763 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_176787.5(PIGN):c.996T>G (p.Ile332Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1060499763 ...