ClinVar Genomic variation as it relates to human health
NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp)
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_004360.5(CDH1):c.2245C>T (p.Arg749Trp)
Variation ID: 418841 Accession: VCV000418841.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 68828254 (GRCh38) [ NCBI UCSC ] 16: 68862157 (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 Apr 29, 2017 May 1, 2024 Aug 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004360.5:c.2245C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004351.1:p.Arg749Trp missense NM_001317184.2:c.2062C>T NP_001304113.1:p.Arg688Trp missense NM_001317185.2:c.697C>T NP_001304114.1:p.Arg233Trp missense NM_001317186.2:c.280C>T NP_001304115.1:p.Arg94Trp missense NC_000016.10:g.68828254C>T NC_000016.9:g.68862157C>T NG_008021.1:g.95963C>T LRG_301:g.95963C>T LRG_301t1:c.2245C>T - Protein change
- R749W, R688W, R233W, R94W
- Other names
- NM_004360.4(CDH1):c.2245C>T
- p.R749W
- NM_004360.5(CDH1):c.2245C>T
- Canonical SPDI
- NC_000016.10:68828253: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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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CDH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4387 | 4476 |
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
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 8, 2020 | RCV000479819.6 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 27, 2024 | RCV000663000.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2023 | RCV000774774.11 | |
Uncertain significance (1) |
reviewed by expert panel
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Aug 28, 2023 | RCV003328355.3 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001355065.3 |
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
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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
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
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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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Uncertain Significance
(Aug 28, 2023)
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reviewed by expert panel
Method: curation
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CDH1-related diffuse gastric and lobular breast cancer syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen CDH1 Variant Curation Expert Panel
Accession: SCV000864626.5
First in ClinVar: Jan 22, 2019 Last updated: Apr 15, 2024 |
Comment:
The NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp) variant is a missense variant in exon 14 and results in the change of an Arginine to a Tryptophan. This variant is … (more)
The NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp) variant is a missense variant in exon 14 and results in the change of an Arginine to a Tryptophan. This variant is present in <1/100,000 alleles in the ExAC and gnomAD cohort (PM2_Supporting). Furthermore, it has been observed in > 10 individuals (34) without DGC, SRC tumours or LBC and whose families do not suggest HDGC. This variant has been reported in four families meeting HDGC clinical criteria, however, this represents only 11% of all families carrying this variant (threshold is 30% to consider applying PS4). Given that multiple families with this variants meet the HDGC criteria, CDH1-VCEP recommended not to apply BS2 code. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. (less)
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Uncertain significance
(Feb 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786002.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Apr 25, 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: SCV000566200.5
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
This variant is denoted CDH1 c.2245C>T at the cDNA level, p.Arg749Trp (R749W) at the protein level, and results in the change of an Arginine to … (more)
This variant is denoted CDH1 c.2245C>T at the cDNA level, p.Arg749Trp (R749W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been suggested in several in vitro based assays to result in reduced E-cadherin surface expression and cell-cell adhesion, as well as increased cell motility and invasion compared to wild type controls (Kaurah 2007, Simoes-Correia 2008, Mateus 2009, Figueiredo 2013). While CDH1 Arg749Trp has also been observed in a family with three cases of gastric cancer, two of which are reported as diffuse gastric cancer, segregation analysis was not completed (Kaurah 2007). CDH1 Arg749Trp was not observed in large population cohorts. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Arg749Trp is located in the cytoplasmic domain and Hakai p120-catenin binding regions (Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. While there are in vitro functional assays suggesting pathogenicity, internal observations at this laboratory and other clinical laboratories are not suggestive of hereditary diffuse gastric cancer. Based on currently available evidence, it is unclear whether CDH1 Arg749Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Dec 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000908759.3
First in ClinVar: May 20, 2019 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces arginine with tryptophan at codon 749 of the CDH1 protein. Functional studies have shown the mutant protein to be defective in … (more)
This missense variant replaces arginine with tryptophan at codon 749 of the CDH1 protein. Functional studies have shown the mutant protein to be defective in cell surface expression, cell adhesion, motility and cell invasion ability (PMID 17545690, 18772194, 19268661, 22850631). The severity of the defect differs broadly. This variant has been reported in a family with five individuals affected with gastric cancer (ages 36-49), two of whom with diffuse cancer, but each individual's genotype was not provided (PMID: 17545690). This variant has been observed in an individual affected with breast cancer (PMID: 30653559). This variant has been identified in 1/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 25, 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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888034.2
First in ClinVar: Apr 29, 2017 Last updated: Jan 01, 2022 |
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Uncertain significance
(May 08, 2020)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503292.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Likely pathogenic
(Jul 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV002523186.1 First in ClinVar: Jun 07, 2022 Last updated: Jun 07, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Fetal growth restriction (present) , Polyhydramnios (present) , Abnormal maternal serum screening (present) , Wide mouth (present) , Hypertelorism (present) , Epistaxis (present) , Wide … (more)
Fetal growth restriction (present) , Polyhydramnios (present) , Abnormal maternal serum screening (present) , Wide mouth (present) , Hypertelorism (present) , Epistaxis (present) , Wide nasal bridge (present) , Broad nasal tip (present) , Deeply set eye (present) , Exotropia (present) , Autism (present) , Self-mutilation (present) , Eczematoid dermatitis (present) , Hypopigmentation of the skin (present) , Hypotonia (present) , Global developmental delay (present) , Limb hypertonia (present) , Recurrent infections (present) , Bilateral cleft lip and palate (present) , Periventricular heterotopia (present) , Bilateral tonic-clonic seizure with focal onset (present) , Hyperopia, high (present) , Feeding difficulties (present) , Infantile spasms (present) , Decreased circulating level of specific antibody (present) , Scleral staphyloma (present) , Tip-toe gait (present) , Arachnoid cyst (present) , Cerebral visual impairment (present) , Macular scar (present) , Hippocampal atrophy (present) (less)
Age: 10-19 years
Sex: male
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Uncertain significance
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001204783.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 749 of the CDH1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 749 of the CDH1 protein (p.Arg749Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 17545690). ClinVar contains an entry for this variant (Variation ID: 418841). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 17545690, 18772194, 19268661, 22850631, 25388006, 34486077). 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)
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Uncertain significance
(Mar 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001175683.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.R749W variant (also known as c.2245C>T), located in coding exon 14 of the CDH1 gene, results from a C to T substitution at nucleotide … (more)
The p.R749W variant (also known as c.2245C>T), located in coding exon 14 of the CDH1 gene, results from a C to T substitution at nucleotide position 2245. The arginine at codon 749 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, located in the intracellular juxtamembrane domain of the CDH1 gene, has been reported in 1 of 38 families diagnosed clinically with hereditary diffuse gastric cancer (HDGC) who were analyzed for CDH1 mutations, however segregation analysis was not completed in this family (Kaurah P et al. JAMA, 2007 Jun;297:2360-72). Several in vitro based studies showed that this variant increased cell motility and invasion compared to wild type controls as well as reduced expression and interaction with E-cadherin (Figueiredo J et al. Eur. J. Hum. Genet., 2013 Mar;21:301-9; Sanches JM et al. Eur. J. Hum. Genet., 2015 Aug;23:1072-9; Mateus AR et al. Exp. Cell Res., 2009 May;315:1393-402; Mestre T et al. Sci Rep, 2016 05;6:25101). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549831.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CDH1 p.Arg749Trp variant was identified in 1 of 76 proband chromosomes (frequency: 0.013) from individuals or families with Diffuse Gastric Cancer, the family included … (more)
The CDH1 p.Arg749Trp variant was identified in 1 of 76 proband chromosomes (frequency: 0.013) from individuals or families with Diffuse Gastric Cancer, the family included 2 cases of diffuse gastric cancer and one case of breast cancer however segregation analysis was not reported (Kaurah 2007). The variant was also identified in dbSNP (ID: rs776975632) as With Uncertain significance allele, in ClinVar and Clinvitae (classified as uncertain significance by GeneDx), Insight Colon Cancer Gene Variant Database, and the Zhejiang Colon Cancer database. GeneDx reports that the variant was observed in patients with phenotypes that are not suggestive of Hereditary Diffuse Gastric Cancer (ClinVar). The variant was not identified in the Cosmic or MutDB, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. Several in vitro functional studies were identified on this variant that suggests that the variant is pathogenic. Multiple studies have displayed that the variant reduces the level of E-cadherin found at the cell membrane and retained the protein in the endoplasmic reticulum (Simoes-Correia 2008, Mateus 2009, Figueiredo 2013, Sanches 2015). One study displayed that the variant produces low total and surface E-cadherin expression, despite the normal RNA levels, because the variant reduces binding of E-cadherin to B-catenin increasing the likelihood of degradation due to ubiquitination (Figueiredo 2013). Kaurah et al. (2007) expressed the c.2245C>T variant in CHO cells and displayed that the variant failed to cause cell aggregation that the wildtype E-cadherin causes and the variant increased the invasion of E-cadherin into collagen matrices at significantly higher rates than wildtype. Additional groups have also displayed increased cell motility due to the c.2245C>T variant (Mateus 2009, Mestre 2016). The p.Arg749 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
Number of individuals with the variant: 1
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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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Integrin β1 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells. | Figueiredo J | Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association | 2022 | PMID: 34486077 |
Quantification of topological features in cell meshes to explore E-cadherin dysfunction. | Mestre T | Scientific reports | 2016 | PMID: 27151223 |
Quantification of mutant E-cadherin using bioimaging analysis of in situ fluorescence microscopy. A new approach to CDH1 missense variants. | Sanches JM | European journal of human genetics : EJHG | 2015 | PMID: 25388006 |
The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC. | Figueiredo J | European journal of human genetics : EJHG | 2013 | PMID: 22850631 |
ADP-ribosylation factor 6 mediates E-cadherin recovery by chemical chaperones. | Figueiredo J | PloS one | 2011 | PMID: 21853084 |
E-cadherin mutations and cell motility: a genotype-phenotype correlation. | Mateus AR | Experimental cell research | 2009 | PMID: 19268661 |
Endoplasmic reticulum quality control: a new mechanism of E-cadherin regulation and its implication in cancer. | Simões-Correia J | Human molecular genetics | 2008 | PMID: 18772194 |
A short guide to hereditary diffuse gastric cancer. | Guilford P | Hereditary cancer in clinical practice | 2007 | PMID: 19725995 |
Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. | Kaurah P | JAMA | 2007 | PMID: 17545690 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c46e3e12-7172-498b-86a7-d9cd9f01bbee | - | - | - | - |
Text-mined citations for rs776975632 ...
HelpRecord last updated May 01, 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.