ClinVar Genomic variation as it relates to human health
NM_013296.5(GPSM2):c.742del (p.Gly249fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_013296.5(GPSM2):c.742del (p.Gly249fs)
Variation ID: 35492 Accession: VCV000035492.22
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 1p13.3 1: 109441560 (GRCh37) [ NCBI UCSC ] 1: 108898938 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 27, 2015 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_013296.5:c.742del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_037428.3:p.Gly249fs frameshift NM_001321038.2:c.742del NP_001307967.1:p.Gly249fs frameshift NM_001321039.3:c.742del NP_001307968.1:p.Gly249fs frameshift NC_000001.11:g.108898939del NC_000001.10:g.109441561del NG_028108.2:g.28590del LRG_1373:g.28590del LRG_1373t1:c.742del LRG_1373p1:p.Gly249fs - Protein change
- G249fs
- Other names
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- Canonical SPDI
- NC_000001.11:108898937:CC:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Comment on variant
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GPSM2 | - | - |
GRCh38 GRCh37 |
224 | 301 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 25, 2023 | RCV000029164.11 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000223985.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2016 | RCV000844707.4 | |
GPSM2-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2018 | RCV004528135.1 |
Submissions - Germline
Classification
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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
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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
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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
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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. |
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Pathogenic
(May 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280912.1
First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016 |
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Pathogenic
(Jun 22, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000861996.1
First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002247435.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Sep 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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GPSM2-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915348.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The GPSM2 c.742delC (p.Gly249GlufsTer32) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly249GlufsTer32 variant has been … (more)
The GPSM2 c.742delC (p.Gly249GlufsTer32) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly249GlufsTer32 variant has been reported in two studies in which it is found in a total of seven individuals with Chudley-McCullough syndrome (CMS) from four families, including in three individuals carrying the variant in a homozygous state (two siblings and one unrelated individual) and four carrying the variant in a compound heterozygous state (two pairs of siblings) (Doherty et al. 2012; Diaz-Horta et al. 2012). The p.Gly249GlufsTer32 variant was also found in a heterozygous state in two unaffected family members (Diaz-Horta et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000363 in the European American population of the Exome Sequencing Project. Based on the evidence and potential impact of frameshift variants, the p.Gly249GlufsTer32 variant is classified as likely pathogenic for GPSM2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jun 09, 2016)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712262.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Gly249fs variant in GPSM2 has been reported in 3 individuals with Chudley- McCullough syndrome (Doherty 2012). Two of these individuals and one of their … (more)
The p.Gly249fs variant in GPSM2 has been reported in 3 individuals with Chudley- McCullough syndrome (Doherty 2012). Two of these individuals and one of their si blings were homozygous and 1 individual and a sibling were compound heterozygous . This variant is predicted to cause a frameshift, which alters the protein?s am ino acid sequence beginning at position 249 and leads to a premature termination codon 32 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss-of-function variants in the GPSM2 gene are as sociated with Chudley-McCullough syndrome, an autosomal recessive condition with congenital hearing loss and brain abnormalities with typically normal cognition . In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Chudley-McCullough syndrome. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001168590.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
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; … (more)
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. (less)
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Chudley-McCullough syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767350.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Chudley-McCullough syndrome (MIM#604213). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (28 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other loss of function variants have previously been reported as pathogenic in individuals with Chudley-McCullough syndrome (MIM#604213) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple individuals with Chudley-McCullough syndrome (MIM#604213) (ClinVar, LOVD, PMID: 22987632). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Chudley-McCullough syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002783638.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 25, 2023)
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criteria provided, single submitter
Method: research
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Chudley-McCullough syndrome
Affected status: yes
Allele origin:
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV004012102.1 First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Abnormal brain morphology (present) , Ventriculomegaly (present) , Constipation (present) , Strabismus (present) , Sensorineural hearing loss disorder (present) , Hydrocephalus (present) , Corpus callosum, … (more)
Abnormal brain morphology (present) , Ventriculomegaly (present) , Constipation (present) , Strabismus (present) , Sensorineural hearing loss disorder (present) , Hydrocephalus (present) , Corpus callosum, agenesis of (present) , Polymicrogyria (present) , Global developmental delay (present) (less)
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Pathogenic
(Jun 08, 2012)
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no assertion criteria provided
Method: literature only
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CHUDLEY-MCCULLOUGH SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000051809.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 27, 2015 |
Comment on evidence:
In 2 Mennonite sibs and an unrelated European American patient, all with Chudley-McCullough syndrome (CMCS; 604213), Doherty et al. (2012) identified a homozygous 1-bp deletion … (more)
In 2 Mennonite sibs and an unrelated European American patient, all with Chudley-McCullough syndrome (CMCS; 604213), Doherty et al. (2012) identified a homozygous 1-bp deletion (742delC) in the GPSM2 gene, predicted to cause a frameshift and premature termination (Asn247AsnfsTer34). Affected sibs of Dutch ancestry with the disorder were compound heterozygous for 741delC and a premature termination mutation (S554X; 609245.0005). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808624.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966412.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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GPSM2 mutations in Chudley-McCullough syndrome. | Diaz-Horta O | American journal of medical genetics. Part A | 2012 | PMID: 22987632 |
GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. | Doherty D | American journal of human genetics | 2012 | PMID: 22578326 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GPSM2 | - | - | - | - |
Text-mined citations for rs528069912 ...
HelpRecord last updated Aug 18, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
NCBI staff reviewed the sequence information reported in PubMed 22578326 Fig. 2B to determine the location of this allele on the current reference sequence.