VCV000440973.43 - ClinVar

NM_015937.6(PIGT):c.1582G>A (p.Val528Met)

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.

(10)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015937.6(PIGT):c.1582G>A (p.Val528Met)

Variation ID: 440973 Accession: VCV000440973.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 45425671 (GRCh38) [ NCBI UCSC ] 20: 44054311 (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	Jul 9, 2018	Oct 26, 2024	Aug 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015937.6:c.1582G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057021.2:p.Val528Met	missense
NM_001184728.3:c.1414G>A	NP_001171657.1:p.Val472Met	missense
NM_001184729.3:c.1381G>A	NP_001171658.1:p.Val461Met	missense
NM_001184730.3:c.1276G>A	NP_001171659.1:p.Val426Met	missense
NR_047691.2:n.1558G>A		non-coding transcript variant
NR_047692.2:n.1501G>A		non-coding transcript variant
NR_047693.2:n.1497G>A		non-coding transcript variant
NR_047694.2:n.1420G>A		non-coding transcript variant
NR_047695.2:n.1191G>A		non-coding transcript variant
NC_000020.11:g.45425671G>A
NC_000020.10:g.44054311G>A
NG_047154.1:g.14605G>A

... more HGVS ... less HGVS

Protein change

V528M, V426M, V461M, V472M

Other names

Canonical SPDI

NC_000020.11:45425670:G:A

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) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00008

Exome Aggregation Consortium (ExAC) 0.00010

The Genome Aggregation Database (gnomAD), exomes 0.00010

Links

ClinGen: CA9878327 dbSNP: rs771157170 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.
PIGT		-	-	GRCh38 GRCh37	302	315

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.
PIGT-related disorder	not provided (1)	no classification provided	-	RCV000509376.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 30, 2024	RCV000657935.29
Multiple congenital anomalies-hypotonia-seizures syndrome 3	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Aug 23, 2024	RCV000990305.13

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 (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 3 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001141242.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Aug 06, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 3 Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001426153.1 First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020
Pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 3 Affected status: yes Allele origin: maternal	3billion Accession: SCV002012151.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Publications: PubMed (1) PubMed: 34046058 Comment: The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected … (more) The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID:34046058, PM3_VS) It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000102, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.588, 3Cnet: 0.686, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Delayed speech and language development (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , High … (more) Delayed speech and language development (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , High palate (present) , Hypertelorism (present) , Hypothyroidism (present) , Low-set ears (present) , Seizure (present) (less)
Pathogenic (Aug 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 3 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580744.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PS4_MOD, PM3, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: male
Pathogenic (Dec 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 3 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003285129.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28327575‚ 34046058 Comment: This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 528 of the PIGT protein (p.Val528Met). … (more) This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 528 of the PIGT protein (p.Val528Met). This variant is present in population databases (rs771157170, gnomAD 0.02%). This missense change has been observed in individuals with PIGT-related conditions (PMID: 28327575, 34046058). ClinVar contains an entry for this variant (Variation ID: 440973). 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 PIGT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIGT function (PMID: 28327575). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 30, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000779704.5 First in ClinVar: Jul 09, 2018 Last updated: Sep 29, 2024	Comment: Published functional studies suggest a damaging effect, as rescue experiments on PIGT-knockout HEK293 cells demonstrate p.(V528M) results in a mild reduction in the amount of … (more) Published functional studies suggest a damaging effect, as rescue experiments on PIGT-knockout HEK293 cells demonstrate p.(V528M) results in a mild reduction in the amount of CD59 anchored to the cell membrane (PMID: 28327575); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30976099, 34046058, 34162574, 33144682, 28327575, 29310717, 36672771, 32725661, 34469436) (less)
Pathogenic (Apr 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 3 (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001950031.4 First in ClinVar: Oct 02, 2021 Last updated: Oct 13, 2024	Comment: Criteria applied: PM3_VSTR,PS3_MOD,PP3 Clinical Features: Bilateral tonic-clonic seizure (present) , Focal clonic seizure (present) , Epileptic encephalopathy (present) , Global developmental delay (present) , Focal tonic seizure (present) , Severe … (more) Bilateral tonic-clonic seizure (present) , Focal clonic seizure (present) , Epileptic encephalopathy (present) , Global developmental delay (present) , Focal tonic seizure (present) , Severe global developmental delay (present) (less) Sex: female
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249087.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PIGT: PM3:Very Strong, PM2, PP3 Number of individuals with the variant: 10
Pathogenic (Aug 23, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Multiple congenital anomalies-hypotonia-seizures syndrome 3 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005381819.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Publications: PubMed (3) PubMed: 28327575‚ 34046058‚ 30976099 Comment: Variant summary: PIGT c.1582G>A (p.Val528Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: PIGT c.1582G>A (p.Val528Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251258 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PIGT causing Multiple Congenital Anomalies-Hypotonia Syndrome 3, allowing no conclusion about variant significance. c.1582G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Multiple Congenital Anomalies-Hypotonia Syndrome 3 (Bayat_2019, Bayat_2021, Pagnamenta_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34046058, 30976099, 28327575). ClinVar contains an entry for this variant (Variation ID: 440973). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
not provided (-)	no classification provided Method: phenotyping only	PIGT-Related Disorder Affected status: unknown Allele origin: unknown, paternal	GenomeConnect, ClinGen Accession: SCV000606986.4 First in ClinVar: Oct 16, 2017 Last updated: Feb 11, 2022	Comment: Variant identified in multiple registry participants and interpreted, most recently, as Likely pathogenic and reported on 02-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions … (more) Variant identified in multiple registry participants and interpreted, most recently, as Likely pathogenic and reported on 02-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Pregnancy history (present) , Abnormality of eye movement (present) , Abnormality of the nervous system (present) , EEG abnormality (present) , Hypertonia (present) , Generalized … (more) Pregnancy history (present) , Abnormality of eye movement (present) , Abnormality of the nervous system (present) , EEG abnormality (present) , Hypertonia (present) , Generalized hypotonia (present) , Movement disorder (present) , Seizure (present) , Abnormality of facial musculature (present) , Abnormal muscle physiology (present) , Abnormality of the musculature (present) , Abnormal morphology of the pelvis musculature (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2018-02-16 Testing laboratory interpretation: Likely pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Abnormality of coordination (present) , Generalized hypotonia (present) , Joint hypermobility (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs … (more) Abnormality of coordination (present) , Generalized hypotonia (present) , Joint hypermobility (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormal morphology of the pelvis musculature (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2016-07-22 Testing laboratory interpretation: Uncertain significance

Comment:

The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID:34046058, PM3_VS) It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000102, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.588, 3Cnet: 0.686, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 528 of the PIGT protein (p.Val528Met). This variant is present in population databases (rs771157170, gnomAD 0.02%). This missense change has been observed in individuals with PIGT-related conditions (PMID: 28327575, 34046058). ClinVar contains an entry for this variant (Variation ID: 440973). 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 PIGT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIGT function (PMID: 28327575). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies suggest a damaging effect, as rescue experiments on PIGT-knockout HEK293 cells demonstrate p.(V528M) results in a mild reduction in the amount of CD59 anchored to the cell membrane (PMID: 28327575); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30976099, 34046058, 34162574, 33144682, 28327575, 29310717, 36672771, 32725661, 34469436)

Comment:

Variant summary: PIGT c.1582G>A (p.Val528Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251258 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PIGT causing Multiple Congenital Anomalies-Hypotonia Syndrome 3, allowing no conclusion about variant significance. c.1582G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Multiple Congenital Anomalies-Hypotonia Syndrome 3 (Bayat_2019, Bayat_2021, Pagnamenta_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34046058, 30976099, 28327575). ClinVar contains an entry for this variant (Variation ID: 440973). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Variant identified in multiple registry participants and interpreted, most recently, as Likely pathogenic and reported on 02-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
Deep-Phenotyping the Less Severe Spectrum of PIGT Deficiency and Linking the Gene to Myoclonic Atonic Seizures.	Bayat A	Frontiers in genetics	2021	PMID: 34046058
PIGT-CDG, a disorder of the glycosylphosphatidylinositol anchor: description of 13 novel patients and expansion of the clinical characteristics.	Bayat A	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30976099
Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.	Pagnamenta AT	European journal of human genetics : EJHG	2017	PMID: 28327575

Text-mined citations for rs771157170 ...

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 27, 2024

ClinVar Genomic variation as it relates to human health

NM_015937.6(PIGT):c.1582G>A (p.Val528Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs771157170 ...