This sequence change creates a premature translational stop signal (p.Arg731*) in the CTNNA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNNA1 are known to be pathogenic (PMID: 32051609, 34425242). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with a family history of early-onset breast cancer (PMID: 32051609). ClinVar contains an entry for this variant (Variation ID: 659725). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001903.5(CTNNA1):c.2191C>T (p.Arg731Ter)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
4 out of 5 submissions contributed to this classification
Help
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.
5
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001903.5(CTNNA1):c.2191C>T (p.Arg731Ter)
Variation ID: 659725 Accession: VCV000659725.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.2 5: 138930653 (GRCh38) [ NCBI UCSC ] 5: 138266342 (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 Aug 14, 2019 Apr 13, 2025 Jan 22, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001903.5:c.2191C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001894.2:p.Arg731Ter nonsense NM_001290307.3:c.2191C>T NP_001277236.1:p.Arg731Ter nonsense NM_001290309.3:c.1882C>T NP_001277238.1:p.Arg628Ter nonsense NM_001290310.3:c.1822C>T NP_001277239.1:p.Arg608Ter nonsense NM_001290312.1:c.1081C>T NP_001277241.1:p.Arg361Ter nonsense NM_001323982.2:c.2191C>T NP_001310911.1:p.Arg731Ter nonsense NM_001323983.1:c.2191C>T NP_001310912.1:p.Arg731Ter nonsense NM_001323984.2:c.2191C>T NP_001310913.1:p.Arg731Ter nonsense NM_001323985.2:c.2191C>T NP_001310914.1:p.Arg731Ter nonsense NM_001323986.2:c.2098C>T NP_001310915.1:p.Arg700Ter nonsense NM_001323987.1:c.1081C>T NP_001310916.1:p.Arg361Ter nonsense NM_001323988.1:c.1081C>T NP_001310917.1:p.Arg361Ter nonsense NM_001323989.1:c.1081C>T NP_001310918.1:p.Arg361Ter nonsense NM_001323990.1:c.1081C>T NP_001310919.1:p.Arg361Ter nonsense NM_001323991.1:c.1081C>T NP_001310920.1:p.Arg361Ter nonsense NM_001323992.1:c.1081C>T NP_001310921.1:p.Arg361Ter nonsense NM_001323993.1:c.1081C>T NP_001310922.1:p.Arg361Ter nonsense NM_001323994.1:c.1081C>T NP_001310923.1:p.Arg361Ter nonsense NM_001323995.1:c.1081C>T NP_001310924.1:p.Arg361Ter nonsense NM_001323996.1:c.1081C>T NP_001310925.1:p.Arg361Ter nonsense NM_001323997.1:c.1081C>T NP_001310926.1:p.Arg361Ter nonsense NM_001323998.1:c.1081C>T NP_001310927.1:p.Arg361Ter nonsense NM_001323999.1:c.1081C>T NP_001310928.1:p.Arg361Ter nonsense NM_001324000.1:c.1081C>T NP_001310929.1:p.Arg361Ter nonsense NM_001324001.1:c.1081C>T NP_001310930.1:p.Arg361Ter nonsense NM_001324002.1:c.1081C>T NP_001310931.1:p.Arg361Ter nonsense NM_001324003.1:c.1081C>T NP_001310932.1:p.Arg361Ter nonsense NM_001324004.1:c.1081C>T NP_001310933.1:p.Arg361Ter nonsense NM_001324005.1:c.1081C>T NP_001310934.1:p.Arg361Ter nonsense NM_001324006.1:c.742C>T NP_001310935.1:p.Arg248Ter nonsense NM_001324007.1:c.742C>T NP_001310936.1:p.Arg248Ter nonsense NM_001324008.1:c.742C>T NP_001310937.1:p.Arg248Ter nonsense NM_001324009.1:c.742C>T NP_001310938.1:p.Arg248Ter nonsense NM_001324010.1:c.742C>T NP_001310939.1:p.Arg248Ter nonsense NM_001324011.1:c.988C>T NP_001310940.1:p.Arg330Ter nonsense NM_001324012.1:c.838C>T NP_001310941.1:p.Arg280Ter nonsense NM_001324013.1:c.838C>T NP_001310942.1:p.Arg280Ter nonsense NC_000005.10:g.138930653C>T NC_000005.9:g.138266342C>T NG_047029.1:g.182258C>T - Protein change
- R608*, R628*, R731*, R280*, R361*, R700*, R248*, R330*
- Other names
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p.Arg731
- Canonical SPDI
- NC_000005.10:138930652:C:T
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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.
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The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| CTNNA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3271 | 3341 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2025 | RCV000816771.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 5, 2023 | RCV002427020.3 | |
|
CTNNA1-associated FEVR
|
Likely pathogenic (1) |
no assertion criteria provided
|
Aug 3, 2022 | RCV002509555.2 |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 22, 2023 | RCV004569721.1 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jan 22, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000957296.7
First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg731*) in the CTNNA1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg731*) in the CTNNA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNNA1 are known to be pathogenic (PMID: 32051609, 34425242). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with a family history of early-onset breast cancer (PMID: 32051609). ClinVar contains an entry for this variant (Variation ID: 659725). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Uncertain significance
(Apr 05, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002729435.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R731* variant (also known as c.2191C>T), located in coding exon 14 of the CTNNA1 gene, results from a C to T substitution at nucleotide … (more)
The p.R731* variant (also known as c.2191C>T), located in coding exon 14 of the CTNNA1 gene, results from a C to T substitution at nucleotide position 2191. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. (less)
|
|
|
Likely pathogenic
(Dec 22, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Patterned macular dystrophy 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005058590.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Jul 02, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005442980.1
First in ClinVar: Jan 13, 2025 Last updated: Jan 13, 2025 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals referred for hereditary cancer multi-gene panel testing (PMID: 32051609); This variant is associated with the following publications: (PMID: 34425242, 32051609) (less)
|
|
|
Likely pathogenic
(Aug 03, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
CTNNA1-associated FEVR
Affected status: yes
Allele origin:
maternal
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV002818546.2 First in ClinVar: Jan 15, 2023 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Clinical Features:
Abnormal delivery (present) , Poor suck (present) , Neonatal respiratory distress (present) , Neonatal inspiratory stridor (present) , Focal-onset seizure (present) , Caesarean section (present) , Secondary Caesarian section (present) , Brachycephaly (present) , Square face (present) , Abnormal pinna morphology (present) , Anteverted nares (present) , Nystagmus (present) , Hypertrichosis (present) , Global developmental delay (present) , Generalized hypotonia (present) , Growth delay (present) , Dysphagia (present) , Broad-based gait (present) , Focal-onset seizure (present) , Exudative retinopathy (present) , High myopia (present) , Teeth, fused (present) , Pilomatrixoma (present)
Zygosity: Single Heterozygote
Age: 0-9 years
Sex: female
Tissue: Blood
|
Comment:
Comment:
The p.R731* variant (also known as c.2191C>T), located in coding exon 14 of the CTNNA1 gene, results from a C to T substitution at nucleotide position 2191. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Comment:
Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals referred for hereditary cancer multi-gene panel testing (PMID: 32051609); This variant is associated with the following publications: (PMID: 34425242, 32051609)
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:
This sequence change creates a premature translational stop signal (p.Arg731*) in the CTNNA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNNA1 are known to be pathogenic (PMID: 32051609, 34425242). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with a family history of early-onset breast cancer (PMID: 32051609). ClinVar contains an entry for this variant (Variation ID: 659725). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R731* variant (also known as c.2191C>T), located in coding exon 14 of the CTNNA1 gene, results from a C to T substitution at nucleotide position 2191. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Comment:
Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals referred for hereditary cancer multi-gene panel testing (PMID: 32051609); This variant is associated with the following publications: (PMID: 34425242, 32051609)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Cancer predisposition and germline CTNNA1 variants. | Lobo S | European journal of medical genetics | 2021 | PMID: 34425242 |
| Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer. | Clark DF | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32051609 |
Text-mined citations for rs1401839892 ...
HelpThese 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 Apr 13, 2025
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.