NM_000094.4(COL7A1):c.5261dup (p.Gly1755fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 25, 2023
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:: RCV000412717.4

Allele description [Variation Report for NM_000094.4(COL7A1):c.5261dup (p.Gly1755fs)]

NM_000094.4(COL7A1):c.5261dup (p.Gly1755fs)

Gene:

COL7A1:collagen type VII alpha 1 chain [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_000094.4(COL7A1):c.5261dup (p.Gly1755fs)

HGVS:

NC_000003.12:g.48579494dup
NG_007065.1:g.20763dup
NM_000094.4:c.5261dupMANE SELECT
NP_000085.1:p.Gly1755fs
LRG_286:g.20763dup
NC_000003.11:g.48616922_48616923insG
NC_000003.11:g.48616927dup
NM_000094.3:c.5261dupC

Protein change:

G1755fs

Links:

dbSNP: rs1057517723

NCBI 1000 Genomes Browser:

rs1057517723

Molecular consequence:

NM_000094.4:c.5261dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000490491	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jun 10, 2016)	germline	clinical testing	Citation Link,
SCV002242012	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 25, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16439963, 19681861, 27899325, 16971478, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000490491

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jun 10, 2016)

germline

clinical testing

Citation Link,

SCV002242012

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 25, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Molecular epidemiology of hereditary epidermolysis bullosa in a Middle Eastern population.

Abu Sa'd J, Indelman M, Pfendner E, Falik-Zaccai TC, Mizrachi-Koren M, Shalev S, Ben Amitai D, Raas-Rothshild A, Adir-Shani A, Borochowitz ZU, Gershoni-Baruch R, Khayat M, Landau D, Richard G, Bergman R, Uitto J, Kanaan M, Sprecher E.

J Invest Dermatol. 2006 Apr;126(4):777-81. Erratum in: J Invest Dermatol. 2006 Jun;126(6):1427.

PubMed [citation]

PMID:: 16439963

Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort.

Kern JS, Grüninger G, Imsak R, Müller ML, Schumann H, Kiritsi D, Emmert S, Borozdin W, Kohlhase J, Bruckner-Tuderman L, Has C.

Br J Dermatol. 2009 Nov;161(5):1089-97. doi: 10.1111/j.1365-2133.2009.09333.x. Epub 2009 Jun 5.

PubMed [citation]

PMID:: 19681861

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000490491.1

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

Description

The c.5261dupC pathogenic variant in the COL7A1 gene has been reported previously in association with dystrophic epidermolysis bullosa (DEB) in two compound heterozygous patients (Abu Sa'd et al., 2006; Kuttner et al., 2013). It has also been observed in the homozygous state in patients referred for testing at GeneDx. The duplication causes a frameshift starting with codon Glycine 1755, changes this amino acid to a Arginine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Gly1755ArgfsX17 and is located within the triple helical domain of the protein. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the c.5261dupC variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.

#	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

From Invitae, SCV002242012.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372338). This premature translational stop signal has been observed in individuals with epidermolysis bullosa dystrophica (PMID: 16439963, 19681861, 27899325). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly1755Argfs*17) in the COL7A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478).

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

Last Updated: Feb 20, 2024

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