NM_000094.4(COL7A1):c.7060G>C (p.Gly2354Arg) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 9, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001568185.5

Allele description [Variation Report for NM_000094.4(COL7A1):c.7060G>C (p.Gly2354Arg)]

NM_000094.4(COL7A1):c.7060G>C (p.Gly2354Arg)

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.7060G>C (p.Gly2354Arg)

HGVS:

NC_000003.12:g.48572009C>G
NG_007065.1:g.28244G>C
NM_000094.4:c.7060G>CMANE SELECT
NP_000085.1:p.Gly2354Arg
LRG_286t1:c.7060G>C
LRG_286:g.28244G>C
NC_000003.11:g.48609442C>G
NM_000094.3:c.7060G>C

Protein change:

G2354R

Links:

dbSNP: rs748466015

NCBI 1000 Genomes Browser:

rs748466015

Molecular consequence:

NM_000094.4:c.7060G>C - 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
SCV001792011	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 28, 2020)	germline	clinical testing	Citation Link,
SCV004623756	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 9, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7695699, 8218237, 19344236, 22058051, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001792011

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 28, 2020)

germline

clinical testing

Citation Link,

SCV004623756

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 9, 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

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 (5)

Details of each submission

From GeneDx, SCV001792011.1

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

Description

Has not been previously published as pathogenic or benign to our knowledge; Located in the highly conserved Gly-X-Y repeat of the collagenous domain; Glycine substitution variants in this region of the COLVII protein destabilize the collagen triple helix resulting in skin fragility due to poor anchoring of the basement membrane to the underlying dermis (Pfendner and Lucky, 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function

#	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, SCV004623756.1

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2354 of the COL7A1 protein (p.Gly2354Arg). This variant is present in population databases (rs748466015, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COL7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1202489). 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 with a positive predictive value of 95%. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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