NM_024989.4(PGAP1):c.2274C>G (p.Tyr758Ter) AND Intellectual disability, autosomal recessive 42

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 23, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000986966.3

Allele description [Variation Report for NM_024989.4(PGAP1):c.2274C>G (p.Tyr758Ter)]

NM_024989.4(PGAP1):c.2274C>G (p.Tyr758Ter)

Gene:

PGAP1:post-GPI attachment to proteins inositol deacylase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q33.1

Genomic location:

Preferred name:

NM_024989.4(PGAP1):c.2274C>G (p.Tyr758Ter)

HGVS:

NC_000002.12:g.196845894G>C
NG_046780.1:g.86102C>G
NM_001321099.2:c.1752C>G
NM_001321100.2:c.1107C>G
NM_024989.4:c.2274C>GMANE SELECT
NP_001308028.1:p.Tyr584Ter
NP_001308029.1:p.Tyr369Ter
NP_079265.2:p.Tyr758Ter
NC_000002.11:g.197710618G>C

Protein change:

Y369*

Links:

dbSNP: rs1576086299

NCBI 1000 Genomes Browser:

rs1576086299

Molecular consequence:

NM_001321099.2:c.1752C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001321100.2:c.1107C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_024989.4:c.2274C>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Intellectual disability, autosomal recessive 42 (NEDDSBA)
Synonyms:: GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 9; Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities
Identifiers:: MONDO: MONDO:0014348; MedGen: C4014343; Orphanet: 88616; OMIM: 615802

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001136129	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV003256538	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 23, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17711852, 26050939, 27848944, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001136129

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Likely pathogenic
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV003256538

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 23, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

PGAP1 knock-out mice show otocephaly and male infertility.

Ueda Y, Yamaguchi R, Ikawa M, Okabe M, Morii E, Maeda Y, Kinoshita T.

J Biol Chem. 2007 Oct 19;282(42):30373-80. Epub 2007 Aug 20.

PubMed [citation]

PMID:: 17711852

Loss of function of PGAP1 as a cause of severe encephalopathy identified by Whole Exome Sequencing: Lessons of the bioinformatics pipeline.

Granzow M, Paramasivam N, Hinderhofer K, Fischer C, Chotewutmontri S, Kaufmann L, Evers C, Kotzaeridou U, Rohrschneider K, Schlesner M, Sturm M, Pinkert S, Eils R, Bartram CR, Bauer P, Moog U.

Mol Cell Probes. 2015 Oct;29(5):323-9. doi: 10.1016/j.mcp.2015.05.012. Epub 2015 Jun 4.

PubMed [citation]

PMID:: 26050939

See all PubMed Citations (4)

Details of each submission

From Mendelics, SCV001136129.1

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

From Invitae, SCV003256538.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 801847). This variant has not been reported in the literature in individuals affected with PGAP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr758*) in the PGAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PGAP1 are known to be pathogenic (PMID: 17711852, 26050939, 27848944).

#	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

Last Updated: May 7, 2024

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