rs1555515445

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_004360.5(CDH1):c.760G>A(p.Asp254Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D254Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

CDH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a domain Cadherin 1 (size 107) in uniprot entity CADH1_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_004360.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-68810269-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 16-68810269-G-A is Pathogenic according to our data. Variant chr16-68810269-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 834043.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr16-68810269-G-A is described in Lovd as [Pathogenic]. Variant chr16-68810269-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5 link	c.760G>A	p.Asp254Asn	missense_variant	Exon 6 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 link	c.760G>A	p.Asp254Asn	missense_variant	Exon 6 of 15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 link	c.-856G>A		5_prime_UTR_variant	Exon 6 of 16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 link	c.-1060G>A		5_prime_UTR_variant	Exon 6 of 15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.760G>A	p.Asp254Asn	missense_variant	Exon 6 of 16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CDH1-related disorder

Pathogenic:1

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH1 c.760G>A variant is predicted to result in the amino acid substitution p.Asp254Asn. This variant has been reported in multiple individuals with nonsyndromic cleft lip and/or palate (Figure S1, Brito et al. 2015. PubMed ID: 26123647; Table 1, de novo, Cox et al. 2018. PubMed ID: 29805042; Table S3, de novo Bishop et al. 2020. PubMed ID: 32574564; Alvizi et al. 2023. PubMed ID: 37225711), and blepharocheilodontic syndrome (Table 2, Kievit et al. 2018. PubMed ID: 29348693). This variant has segregated within families with incomplete penetrance (Brito et al. 2015. PubMed ID: 26123647; Alvizi et al. 2023. PubMed ID: 37225711; Kievit et al. 2018. PubMed ID: 29348693). This variant has not been reported in a large population database, indicating this variant is rare. An in vivo experimental study in zebrafish suggests this variant affects craniofacial development and an in vitro experimental study suggests that this variant has a dominant negative effect (Figure 3 and 4, Kievit et al. 2018. PubMed ID: 29348693). An alternate nucleotide substitution affecting the same amino acid (p.Asp254Tyr) has been reported in an individual with nonsyndromic cleft lip and/or palate (Figure 1, Pan et al. 2021. PubMed ID: 34592648), and blepharocheilodontic syndrome (Figure 1, Ghoumid et al. 2017. PubMed ID: 28301459). In summary, the c.760G>A (p.Asp254Asn) variant is interpreted as pathogenic. -

Cleft lip with or without cleft palate

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1

Sep 18, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 254 of the CDH1 protein (p.Asp254Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cleft lip/palate or blepharocheilodontic syndrome (PMID: 26123647, 29348693, 29805042, 32574564). ClinVar contains an entry for this variant (Variation ID: 834043). 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: 26123647, 29348693). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;T;T;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.5

H;.;.;.;H

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.6

D;.;.;.;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.022

D;.;.;.;D

Sift4G

Uncertain

0.023

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.98

MutPred

0.88

Gain of glycosylation at T251 (P = 0.1319);Gain of glycosylation at T251 (P = 0.1319);Gain of glycosylation at T251 (P = 0.1319);Gain of glycosylation at T251 (P = 0.1319);Gain of glycosylation at T251 (P = 0.1319);

MVP

0.97

MPC

0.89

ClinPred

0.99

GERP RS

5.2

Varity_R

0.77

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over