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NM_000094.4(COL7A1):c.1732C>T (p.Arg578Ter) AND Recessive dystrophic epidermolysis bullosa

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Aug 30, 2017
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:
RCV000578166.5

Allele description [Variation Report for NM_000094.4(COL7A1):c.1732C>T (p.Arg578Ter)]

NM_000094.4(COL7A1):c.1732C>T (p.Arg578Ter)

Gene:
COL7A1:collagen type VII alpha 1 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p21.31
Genomic location:
Preferred name:
NM_000094.4(COL7A1):c.1732C>T (p.Arg578Ter)
HGVS:
  • NC_000003.12:g.48590721G>A
  • NG_007065.1:g.9532C>T
  • NM_000094.4:c.1732C>TMANE SELECT
  • NP_000085.1:p.Arg578Ter
  • NP_000085.1:p.Arg578Ter
  • LRG_286t1:c.1732C>T
  • LRG_286:g.9532C>T
  • LRG_286p1:p.Arg578Ter
  • NC_000003.11:g.48628154G>A
  • NM_000094.3:c.1732C>T
Protein change:
R578*
Links:
dbSNP: rs144023803
NCBI 1000 Genomes Browser:
rs144023803
Molecular consequence:
  • NM_000094.4:c.1732C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Recessive dystrophic epidermolysis bullosa (RDEB)
Synonyms:
EPIDERMOLYSIS BULLOSA DYSTROPHICA, AUTOSOMAL RECESSIVE; DYSTROPHIC EPIDERMOLYSIS BULLOSA, AUTOSOMAL RECESSIVE; EPIDERMOLYSIS BULLOSA DYSTROPHICA, HALLOPEAU-SIEMENS TYPE; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009179; MedGen: C0079474; Orphanet: 79408; Orphanet: 79409; OMIM: 226600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000680020Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Aug 30, 2017)
maternalclinical testing

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

SCV001456298Natera, Inc.
no assertion criteria provided
Pathogenic
(Sep 16, 2020)
germlineclinical testing

SCV005042539Neuberg Centre For Genomic Medicine, NCGM
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicgermlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedmaternalyes21not provided3not providedclinical testing

Citations

PubMed

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV000680020.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)

Description

The NM_000094.3(COL7A1):c.1732C>T heterozygous nonsense variant was identified in exon 13 of COL7A1. This nonsense variant creates a stop codon at amino acid position 578, NP_000085.1(COL7A1):p.(Arg578*). This is predicted to result in loss of protein function either through truncation (~75% of the protein, including multiple triple helix repeats) or nonsense-mediated decay. This variant is present in the gnomAD population database at a frequency of 0.004%. It has been previously reported in multiple families with recessive dystrophic epidermolysis bullosa in homozygous or compound heterozygous state (Dunnill et al., (1994), Whittock et al., (1999) and Kern et al., (2006)). In addition, other truncating variants downstream of c.1732C>T in the COL7A1 gene have been reported as pathogenic in individuals with this condition (ClinVar). Based on current information and in association with the NM_000094.3(COL7A1):c.3265C>T nonsense variant, this variant has been classified as PATHOGENIC.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyes3Bloodnot provided2not provided1not provided

From Natera, Inc., SCV001456298.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005042539.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The stop gained c.1732C>T p.Arg578Ter variant in COL7A1 gene has been previously reported in homozygous, heterozygous and compound heterozygous states in multiple individuals affected with Epidermolysis bullosa dystrophica Whittock et al., 1999; Alamani et al., 2010; Serafi et al., 2015. The p.Arg578Ter variant has been reported to segregated with disease Serafi et al., 2015. The p.Arg578Ter variant is reported with allele frequency of 0.03% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The nucleotide change c.1732C>T in COL7A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal p.Arg578Ter in the COL7A1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in COL7A1 gene have been previously reported to be pathogenic Varki et al., 2007. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024