NM_000094.4(COL7A1):c.7723G>A (p.Gly2575Arg) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 18, 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:: RCV000255334.5

Allele description [Variation Report for NM_000094.4(COL7A1):c.7723G>A (p.Gly2575Arg)]

NM_000094.4(COL7A1):c.7723G>A (p.Gly2575Arg)

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.7723G>A (p.Gly2575Arg)

HGVS:

NC_000003.12:g.48568819C>T
NG_007065.1:g.31434G>A
NM_000094.3:c.[7723G>A]
NM_000094.4:c.7723G>AMANE SELECT
NP_000085.1:p.Gly2575Arg
NP_000085.1:p.Gly2575Arg
LRG_286t1:c.7723G>A
LRG_286:g.31434G>A
LRG_286p1:p.Gly2575Arg
NC_000003.11:g.48606252C>T
NM_000094.3:c.7723G>A
NM_000094.3:c.[7723G>A]
Q02388:p.Gly2575Arg

Protein change:

G2575R

Links:

UniProtKB: Q02388#VAR_001831; dbSNP: rs760891216

NCBI 1000 Genomes Browser:

rs760891216

Molecular consequence:

NM_000094.4:c.7723G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000321513	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Feb 27, 2016)	germline	clinical testing	Citation Link,
SCV001589398	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 18, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7695699, 8218237, 19344236, 22058051, 8592061, 16971478, 18450758, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321513

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Feb 27, 2016)

germline

clinical testing

Citation Link,

SCV001589398

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 18, 2023)

germline

clinical testing

PubMed (8)
[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

Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution.

Bella J, Eaton M, Brodsky B, Berman HM.

Science. 1994 Oct 7;266(5182):75-81.

PubMed [citation]

PMID:: 7695699

Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence.

Long CG, Braswell E, Zhu D, Apigo J, Baum J, Brodsky B.

Biochemistry. 1993 Nov 2;32(43):11688-95.

PubMed [citation]

PMID:: 8218237

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000321513.7

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

Description

The Gly2575Arg pathogenic variant in the COL7A1 gene has been reported previously (Shimizu et al 1996, Pfendner et al 2003, Kern et al., 2006, Saito et al., 2008). The Gly2575Arg variant is reported to affected disulfide bonding between colVII monomers to form the trimer mature col7 fibers Woodley et al., 2008) and also affects the formation of heterotypic trimers more than homotypic ones (Brittingham et al 2005). The Gly2575Arg variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Gly2575Arg 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Numerous Glycine substitution variants throughout the COL7A1 gene and missense variants in nearby residues (R2580C) have been reported in the Human Gene Mutation Database in association with DEB (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Gly2575Arg as a pathogenic variant.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001589398.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2575 of the COL7A1 protein (p.Gly2575Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dystrophic epidermolysis bullosa (PMID: 8592061, 16971478). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265078). 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. Experimental studies have shown that this missense change affects COL7A1 function (PMID: 18450758). 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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