NM_000094.4(COL7A1):c.6082G>A AND not provided

Clinical significance:Pathogenic (Last evaluated: Oct 3, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000435332.5

Allele description [Variation Report for NM_000094.4(COL7A1):c.6082G>A]

NM_000094.4(COL7A1):c.6082G>A

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.6082G>A
HGVS:
  • NC_000003.12:g.48575437C>T
  • NG_007065.1:g.24816G>A
  • NM_000094.3:c.6082G>A
  • NM_000094.4:c.6082G>AMANE SELECT
  • NP_000085.1:p.Gly2028Arg
  • LRG_286t1:c.6082G>A
  • LRG_286:g.24816G>A
  • LRG_286p1:p.Gly2028Arg
  • NC_000003.11:g.48612870C>T
  • p.Gly2028Arg
Protein change:
G2028R
Links:
dbSNP: rs762162799
NCBI 1000 Genomes Browser:
rs762162799
Molecular consequence:
  • NM_000094.3:c.6082G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000516585GeneDxcriteria provided, single submitter
Pathogenic
(Dec 31, 2018)
germlineclinical testing

Citation Link,

SCV001246190CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
Pathogenic
(May 1, 2018)
germlineclinical testing

Citation Link,

SCV001578935Invitaecriteria provided, single submitter
Pathogenic
(Oct 3, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes2not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A de novo glycine substitution mutation in the collagenous domain of COL7A1 in dominant dystrophic epidermolysis bullosa.

Lee JY, Li C, Chao SC, Pulkkinen L, Uitto J.

Arch Dermatol Res. 2000 Apr;292(4):159-63.

PubMed [citation]
PMID:
10836608

Neonatal epidermolysis bullosa: lessons to learn about genetic counseling.

Chong SC, Hon KL, Yuen LYP, Choi PCL, Ng WGG, Chiu TW.

J Dermatolog Treat. 2021 Feb;32(1):29-32. doi: 10.1080/09546634.2018.1527999. Epub 2020 Nov 2.

PubMed [citation]
PMID:
30280950
See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000516585.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The G2028R variant in the COL7A1 gene has been reported previously in both autosomal dominant and autosomal recessive dystrophic epidermolysis bullosa (DEB), including one individual with DDEB in whom the G2028R variant occurred de novo (Lee et al., 2000; Murata et al., 2000; Nakamura et al., 2004; Varki et al., 2007; Lucky et al., 2018). This variant is not observed in large population cohorts (Lek et al., 2016). The G2028R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, as this substitution occurs at a Glycine position of the canonical Gly-X-Y repeat in the collagenous domain of the COLVII protein. Other missense variants in the same Glycine residue (G2028W, G2028A, G2028E) have also been reported in the Human Gene Mutation Database in association with DEB, supporting the functional importance of this Glycine position (Stenson et al., 2014). Glycine substitutions in this region of the protein destabilize the COLVII triple helix yielding fragile and unstable anchoring fibrils that are unable to adequately anchor the basement membrane of the epidermis to the dermis, resulting in skin fragility. We interpret G2028R as a pathogenic variant.

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

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001246190.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From Invitae, SCV001578935.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces glycine with arginine at codon 2028 of the COL7A1 protein (p.Gly2028Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant and autosomal recessive dystrophic epidermolysis bullosa (PMID: 10836608, 30280950, 19665875, 18429782). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 379476). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL7A1 protein function. This variant disrupts the triple helix domain of COL7A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and variants at these glycine residues in COL7A1 are more frequently observed in individuals with disease than in the general population (PMID: 22058051). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 8, 2021

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