ClinVar Genomic variation as it relates to human health
NM_005199.5(CHRNG):c.753_754del (p.Val253fs)
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_005199.5(CHRNG):c.753_754del (p.Val253fs)
Variation ID: 18342 Accession: VCV000018342.44
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 2q37.1 2: 232543030-232543031 (GRCh38) [ NCBI UCSC ] 2: 233407740-233407741 (GRCh37) [ 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 Nov 9, 2015 Feb 20, 2024 Jan 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005199.5:c.753_754del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005190.4:p.Val253fs frameshift NM_005199.5:c.753_754delCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_005199.4:c.753_754del NC_000002.12:g.232543030_232543031del NC_000002.11:g.233407740_233407741del NG_012954.2:g.8339_8340del LRG_1275:g.8339_8340del LRG_1275t1:c.753_754del LRG_1275p1:p.Val253fs NP_005190.4:p.Val253Alafs - Protein change
- V253fs
- Other names
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- Canonical SPDI
- NC_000002.12:232543029:CT:
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00018
The Genome Aggregation Database (gnomAD) 0.00026
Trans-Omics for Precision Medicine (TOPMed) 0.00031
1000 Genomes Project 30x 0.00062
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00176
The Genome Aggregation Database (gnomAD), exomes 0.00016
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 | ||
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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
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. |
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CHRNG | - | - |
GRCh38 GRCh37 |
332 | 528 |
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. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2023 | RCV000020010.33 | |
Pathogenic (3) |
criteria provided, single submitter
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Oct 28, 2019 | RCV000201795.7 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000282633.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2016 | RCV000622703.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814005.2 | |
CHRNG-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Oct 26, 2018 | RCV000778602.5 |
Pathogenic (1) |
criteria provided, single submitter
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Jan 20, 2022 | RCV002490395.1 |
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. |
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Pathogenic
(Feb 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lethal multiple pterygium syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003845110.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: CHRNG c.753_754delCT (p.Val253AlafsX44) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CHRNG c.753_754delCT (p.Val253AlafsX44) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 251490 control chromosomes. c.753_754delCT has been reported in the literature in multiple individuals affected with lethal and Escobar variant multiple pterygium syndrome. These data indicate that the variant is very likely to be associated with disease. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive multiple pterygium syndrome
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368372.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
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Pathogenic
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905677.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Clinical Features:
Micrognathia (present) , Low-set ears (present) , Polyhydramnios (present) , Congenital vertical talus (present) , Esophageal atresia (present) , Flat face (present)
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Pathogenic
(Jan 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lethal multiple pterygium syndrome
Autosomal recessive multiple pterygium syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002799657.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741891.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Arthrogryposis multiplex congenita (present) , Scoliosis (present) , Visual impairment (present) , Motor delay (present) , Short stature (present)
Sex: female
Ethnicity/Population group: Asian/Pakistani
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Pathogenic
(Jul 18, 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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Revvity Omics, Revvity
Accession: SCV002019314.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 04, 2024)
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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: SCV003195503.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val253Alafs*44) in the CHRNG gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Val253Alafs*44) in the CHRNG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHRNG are known to be pathogenic (PMID: 16826520). This variant is present in population databases (rs767503038, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with lethal and Escobar variant multiple pterygium syndrome (PMID: 16826531, 22167768, 24038971, 25608830, 27245440). ClinVar contains an entry for this variant (Variation ID: 18342). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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CHRNG-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914910.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CHRNG c.753_754delCT (p.Val253AlafsTer44) variant results in a frameshift, and is predicted to result in premature termination of the protein. This variant has been reported … (more)
The CHRNG c.753_754delCT (p.Val253AlafsTer44) variant results in a frameshift, and is predicted to result in premature termination of the protein. This variant has been reported in six studies and is found in a total of seven probands including four in a homozygous state and three in a compound heterozygous state (Morgan et al. 2006; Vogt et al. 2012; Robinson et al. 2013; Chong et al. 2015; Kariminejad et al. 2016; Bayram et al. 2016). The variant has been described in probands with both lethal multiple pterygium syndrome and non-lethal (Escobar) phenotypes. Control data are unavailable for this variant, but it is reported at a frequency of 0.00038 in the African population of the Exome Aggregation Consortium. Based on the evidence, the p.Val253AlafsTer44 variant is classified as pathogenic for CHRNG-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
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of prenatal development or birth
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755631.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lethal multiple pterygium syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521476.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). Frameshift: predicted to result in a loss … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000018342). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Flexion contracture (present) , Abnormal heart morphology (present) , Abnormality of the diaphragm (present)
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Pathogenic
(Apr 16, 2021)
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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: SCV000329801.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25957469, 25608830, 30868735, 24038971, 22167768, 34426522, 31589614, 33250842, 32587836, 16826531) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Lethal multiple pterygium syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171349.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The frameshift c.753_754del(p.Val253AlafsTer44) variant in CHRNG gene has been reported previously in homozygous and compound heterozygous states in individual(s) affected with Multiple pterygium syndrome (Chong … (more)
The frameshift c.753_754del(p.Val253AlafsTer44) variant in CHRNG gene has been reported previously in homozygous and compound heterozygous states in individual(s) affected with Multiple pterygium syndrome (Chong JX, et. al., 2015; Kariminejad A, et. al., 2016). The p.Val253AlafsTer44 variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Valine 253, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 44 of the new reading frame, denoted p.Val253AlafsTer44. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Autosomal recessive multiple pterygium syndrome
This variant was identified in an
(more...)
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV001167471.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Number of individuals with the variant: 12
Family history: yes
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Pathogenic
(Apr 01, 2015)
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no assertion criteria provided
Method: literature only
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MULTIPLE PTERYGIUM SYNDROME, LETHAL TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000040308.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2015 |
Comment on evidence:
In a Turkish family with parental consanguinity, Morgan et al. (2006) demonstrated that the lethal form of multiple pterygium syndrome (LMPS; 253290) was caused by … (more)
In a Turkish family with parental consanguinity, Morgan et al. (2006) demonstrated that the lethal form of multiple pterygium syndrome (LMPS; 253290) was caused by a deletion mutation in exon 7 of the CHRNG gene, 753_754delCT (Pro251ProfsTer46). For discussion of the 2-bp deletion in the CHRNG gene that was found in compound heterozygous state in patients with Escobar syndrome (EVMPS; 265000) by Seo et al. (2015), see 100730.0009. (less)
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Pathogenic
(Apr 01, 2015)
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no assertion criteria provided
Method: literature only
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ESCOBAR SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000256538.1
First in ClinVar: Nov 09, 2015 Last updated: Nov 09, 2015 |
Comment on evidence:
In a Turkish family with parental consanguinity, Morgan et al. (2006) demonstrated that the lethal form of multiple pterygium syndrome (LMPS; 253290) was caused by … (more)
In a Turkish family with parental consanguinity, Morgan et al. (2006) demonstrated that the lethal form of multiple pterygium syndrome (LMPS; 253290) was caused by a deletion mutation in exon 7 of the CHRNG gene, 753_754delCT (Pro251ProfsTer46). For discussion of the 2-bp deletion in the CHRNG gene that was found in compound heterozygous state in patients with Escobar syndrome (EVMPS; 265000) by Seo et al. (2015), see 100730.0009. (less)
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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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The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance. | Pehlivan D | American journal of human genetics | 2019 | PMID: 31230720 |
Truncating CHRNG mutations associated with interfamilial variability of the severity of the Escobar variant of multiple pterygium syndrome. | Kariminejad A | BMC genetics | 2016 | PMID: 27245440 |
Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin. | Bayram Y | The Journal of clinical investigation | 2016 | PMID: 26752647 |
Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. | Chong JX | American journal of human genetics | 2015 | PMID: 25957469 |
Rare cases of congenital arthrogryposis multiplex caused by novel recurrent CHRNG mutations. | Seo J | Journal of human genetics | 2015 | PMID: 25608830 |
Neuromotor synapses in Escobar syndrome. | Robinson KG | American journal of medical genetics. Part A | 2013 | PMID: 24038971 |
CHRNG genotype-phenotype correlations in the multiple pterygium syndromes. | Vogt J | Journal of medical genetics | 2012 | PMID: 22167768 |
Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome. | Morgan NV | American journal of human genetics | 2006 | PMID: 16826531 |
Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. | Hoffmann K | American journal of human genetics | 2006 | PMID: 16826520 |
Text-mined citations for rs767503038 ...
HelpRecord last updated Jun 23, 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.