NM_000213.5(ITGB4):c.2783-2A>G AND Junctional epidermolysis bullosa with pyloric atresia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 26, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000190599.8

Allele description [Variation Report for NM_000213.5(ITGB4):c.2783-2A>G]

NM_000213.5(ITGB4):c.2783-2A>G

Gene:

ITGB4:integrin subunit beta 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.1

Genomic location:

Preferred name:

NM_000213.5(ITGB4):c.2783-2A>G

HGVS:

NC_000017.11:g.75742580A>G
NG_007372.1:g.26146A>G
NG_007372.2:g.26123A>G
NM_000213.5:c.2783-2A>GMANE SELECT
NM_001005619.1:c.2783-2A>G
NM_001005731.3:c.2783-2A>G
NM_001321123.2:c.2783-2A>G
NC_000017.10:g.73738661A>G
NM_000213.3:c.2783-2A>G

Links:

dbSNP: rs758551913

NCBI 1000 Genomes Browser:

rs758551913

Molecular consequence:

NM_000213.5:c.2783-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001005619.1:c.2783-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001005731.3:c.2783-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001321123.2:c.2783-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Junctional epidermolysis bullosa with pyloric atresia
Synonyms:: EB-PA-ACC; Epidermolysis bullosa with pyloric atresia; Carmi syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009183; MedGen: C5676875; Orphanet: 79403; OMIM: 226730

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000245627	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Apr 23, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001547442	Biomedical Innovation Departament, CIEMAT	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 26, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004101519	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000245627

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Apr 23, 2014)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001547442

Biomedical Innovation Departament, CIEMAT

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 26, 2018)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV004101519

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq, SCV000245627.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The c.2783-2A>G variant in ITGB4 has not been reported in individuals with epidermolysis bullosa with pyloric atresia and was absent from large population studies. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, although additional studies are required to fully establish its clinical significance, the c.2783-2A>G variant is likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Biomedical Innovation Departament, CIEMAT, SCV001547442.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004101519.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The splice site variant c.2783-2A>G in ITGB4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Likely Pathogenic/Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0003995% is reported in gnomAD. The nucleotide change in ITGB4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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