NM_013296.5(GPSM2):c.742del (p.Gly249fs) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Nov 27, 2023
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:: RCV000223985.11

Allele description

NM_013296.5(GPSM2):c.742del (p.Gly249fs)

Gene:

GPSM2:G protein signaling modulator 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1p13.3

Genomic location:

Preferred name:

NM_013296.5(GPSM2):c.742del (p.Gly249fs)

HGVS:

NC_000001.11:g.108898939del
NG_028108.2:g.28590del
NM_001321038.2:c.742del
NM_001321039.3:c.742del
NM_013296.5:c.742delMANE SELECT
NP_001307967.1:p.Gly249fs
NP_001307968.1:p.Gly249fs
NP_037428.3:p.Gly249fs
LRG_1373t1:c.742del
LRG_1373:g.28590del
LRG_1373p1:p.Gly249fs
NC_000001.10:g.109441560del
NC_000001.10:g.109441561del
NM_013296.4:c.742delC
p.Gly249GlufsX32

Note:

NCBI staff reviewed the sequence information reported in PubMed 22578326 Fig. 2B to determine the location of this allele on the current reference sequence.

Protein change:

G249fs

Links:

OMIM: 609245.0004; dbSNP: rs528069912

NCBI 1000 Genomes Browser:

rs528069912

Molecular consequence:

NM_001321038.2:c.742del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001321039.3:c.742del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_013296.5:c.742del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000280912	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000861996	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Jun 22, 2018)	germline	clinical testing	Citation Link,
SCV001168590	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Nov 12, 2018)	germline	clinical testing	Citation Link,
SCV001808624	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001966412	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002247435	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22987632, 22578326, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

GPSM2 mutations in Chudley-McCullough syndrome.

Diaz-Horta O, Sirmaci A, Doherty D, Nance W, Arnos K, Pandya A, Tekin M.

Am J Med Genet A. 2012 Nov;158A(11):2972-3. doi: 10.1002/ajmg.a.35636. Epub 2012 Sep 14. No abstract available.

PubMed [citation]

PMID:: 22987632
PMCID:: PMC3657751

See all PubMed Citations (4)

Details of each submission

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000280912.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.000186	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000861996.1

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

From GeneDx, SCV001168590.1

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

Description

The c.742delC pathogenic variant in the GPSM2 gene has been reported previously in association with Chudley-McCullough syndrome (Doherty et al., 2012; Diaz-Horta et al., 2012; Almomani et al., 2013). The deletion causes a frameshift starting with codon Glycine 249, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 32 of the new reading frame, denoted Gly249GlufsX32. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is observed in 24/126390 (0.019%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808624.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001966412.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002247435.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Gly249Glufs*32) in the GPSM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GPSM2 are known to be pathogenic (PMID: 22578326, 22987632). This variant is present in population databases (rs528069912, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Chudley-McCullough syndrome (PMID: 22578326). This variant is also known as c.741delC (p.N247NfsX34). ClinVar contains an entry for this variant (Variation ID: 35492). For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 16, 2024

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