VCV000822105.11 - ClinVar

NM_001903.5(CTNNA1):c.1069C>T (p.Arg357Cys)

Germline

Classification

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.

(4)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001903.5(CTNNA1):c.1069C>T (p.Arg357Cys)

Variation ID: 822105 Accession: VCV000822105.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.2 5: 138886218 (GRCh38) [ NCBI UCSC ] 5: 138221907 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Mar 16, 2020	May 1, 2024	Jan 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001903.5:c.1069C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001894.2:p.Arg357Cys	missense
NM_001290307.3:c.1069C>T	NP_001277236.1:p.Arg357Cys	missense
NM_001290309.3:c.760C>T	NP_001277238.1:p.Arg254Cys	missense
NM_001290310.3:c.700C>T	NP_001277239.1:p.Arg234Cys	missense
NM_001290312.1:c.-42C>T		5 prime UTR
NM_001323982.2:c.1069C>T	NP_001310911.1:p.Arg357Cys	missense
NM_001323983.1:c.1069C>T	NP_001310912.1:p.Arg357Cys	missense
NM_001323984.2:c.1069C>T	NP_001310913.1:p.Arg357Cys	missense
NM_001323985.2:c.1069C>T	NP_001310914.1:p.Arg357Cys	missense
NM_001323986.2:c.1069C>T	NP_001310915.1:p.Arg357Cys	missense
NM_001323987.1:c.-42C>T		5 prime UTR
NM_001323988.1:c.-42C>T		5 prime UTR
NM_001323989.1:c.-42C>T		5 prime UTR
NM_001323990.1:c.-42C>T		5 prime UTR
NM_001323991.1:c.-42C>T		5 prime UTR
NM_001323992.1:c.-42C>T		5 prime UTR
NM_001323993.1:c.-42C>T		5 prime UTR
NM_001323994.1:c.-42C>T		5 prime UTR
NM_001323995.1:c.-42C>T		5 prime UTR
NM_001323996.1:c.-42C>T		5 prime UTR
NM_001323997.1:c.-42C>T		5 prime UTR
NM_001323998.1:c.-42C>T		5 prime UTR
NM_001323999.1:c.-42C>T		5 prime UTR
NM_001324000.1:c.-42C>T		5 prime UTR
NM_001324001.1:c.-42C>T		5 prime UTR
NM_001324002.1:c.-42C>T		5 prime UTR
NM_001324003.1:c.-42C>T		5 prime UTR
NM_001324004.1:c.-42C>T		5 prime UTR
NM_001324005.1:c.-42C>T		5 prime UTR
NM_001324006.1:c.-439C>T		5 prime UTR
NM_001324007.1:c.-439C>T		5 prime UTR
NM_001324008.1:c.-439C>T		5 prime UTR
NM_001324009.1:c.-439C>T		5 prime UTR
NM_001324010.1:c.-61+10621C>T		intron variant
NM_001324011.1:c.-42C>T		5 prime UTR
NM_001324012.1:c.-58+10621C>T		intron variant
NM_001324013.1:c.-314C>T		5 prime UTR
NC_000005.10:g.138886218C>T
NC_000005.9:g.138221907C>T
NG_047029.1:g.137823C>T

... more HGVS ... less HGVS

Protein change

R234C, R254C, R357C

Other names

Canonical SPDI

NC_000005.10:138886217:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs758561244 VarSome

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
Gene	OMIM	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	2877	2936

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 8, 2022	RCV001017186.3
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 24, 2024	RCV001047715.7
Patterned macular dystrophy 2	Uncertain significance (1)	criteria provided, single submitter	Sep 29, 2023	RCV003473579.1

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.
Uncertain significance (Jun 08, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001178224.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The p.R357C variant (also known as c.1069C>T), located in coding exon 7 of the CTNNA1 gene, results from a C to T substitution at nucleotide … (more) The p.R357C variant (also known as c.1069C>T), located in coding exon 7 of the CTNNA1 gene, results from a C to T substitution at nucleotide position 1069. The arginine at codon 357 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. (less)
Uncertain significance (Dec 08, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003930774.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32579932, 32051609) (less)
Uncertain significance (Sep 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Patterned macular dystrophy 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211271.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Jan 24, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001211694.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024	Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 357 of the CTNNA1 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 357 of the CTNNA1 protein (p.Arg357Cys). This variant is present in population databases (rs758561244, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CTNNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 822105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CTNNA1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

The p.R357C variant (also known as c.1069C>T), located in coding exon 7 of the CTNNA1 gene, results from a C to T substitution at nucleotide position 1069. The arginine at codon 357 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32579932, 32051609)

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 357 of the CTNNA1 protein (p.Arg357Cys). This variant is present in population databases (rs758561244, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CTNNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 822105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CTNNA1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs758561244 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001903.5(CTNNA1):c.1069C>T (p.Arg357Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs758561244 ...