rs121912844

Positions:

• chr3-48575419-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000094.4(COL7A1):​c.6100G>A​(p.Gly2034Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2034A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.88

Genes affected

COL7A1 (HGNC:2214): (collagen type VII alpha 1 chain) This gene encodes the alpha chain of type VII collagen. The type VII collagen fibril, composed of three identical alpha collagen chains, is restricted to the basement zone beneath stratified squamous epithelia. It functions as an anchoring fibril between the external epithelia and the underlying stroma. Mutations in this gene are associated with all forms of dystrophic epidermolysis bullosa. In the absence of mutations, however, an acquired form of this disease can result from an autoimmune response made to type VII collagen. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000094.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-48575419-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2636169.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL7A1. . Gene score misZ 1.5899 (greater than the threshold 3.09). Trascript score misZ 4.0428 (greater than threshold 3.09). GenCC has associacion of gene with recessive dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa pruriginosa, recessive dystrophic epidermolysis bullosa-generalized other, transient bullous dermolysis of the newborn, epidermolysis bullosa with congenital localized absence of skin and deformity of nails, generalized dominant dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa, nails only, acral dystrophic epidermolysis bullosa, recessive dystrophic epidermolysis bullosa inversa, pretibial dystrophic epidermolysis bullosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 3-48575419-C-T is Pathogenic according to our data. Variant chr3-48575419-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48575419-C-T is described in Lovd as [Pathogenic]. Variant chr3-48575419-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4	c.6100G>A	p.Gly2034Arg	missense_variant	74/119	ENST00000681320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1	c.6100G>A	p.Gly2034Arg	missense_variant	74/119		NM_000094.4	P1
COL7A1	ENST00000328333.12	c.6100G>A	p.Gly2034Arg	missense_variant	73/118	1		P1
COL7A1	ENST00000487017.5	n.2017G>A		non_coding_transcript_exon_variant	39/83	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000418 AC: 1 AN: 238994 Hom.: 0 AF XY: 0.00000763 AC XY: 1 AN XY: 131068

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457728 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 725106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2023	One of the most common pathogenic variants in individuals with autosomal dominant dystrophic epidermolysis bullosa (DDEB); G2034R and G2043R account for up 50% of the DDEB pathogenic variants reported in the largest US cohort (Varki et al., 2007; Pfendner and Lucky, 2018); 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 significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25113066, 21448560, 11874498, 10084325, 9856844, 2653224, 9215684, 31001817, 34046686, 32484238, 11218887, 33274474, 9347800, 16971478, 34543471) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 11, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2034 of the COL7A1 protein (p.Gly2034Arg). This variant is present in population databases (rs121912844, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant epidermolysis bullosa dystrophica (PMID: 9347800). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17450). 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. For these reasons, this variant has been classified as Pathogenic. -

Generalized dominant dystrophic epidermolysis bullosa Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2002	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Epidermolysis bullosa dystrophica Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biomedical Innovation Departament, CIEMAT

Dec 02, 2019

- -

COL7A1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The COL7A1 c.6100G>A variant is predicted to result in the amino acid substitution p.Gly2034Arg. This variant has been reported in many individuals with dystrophic epidermolysis bullosa (see for example, Kon et al. 1997. PubMed ID: 9347800; Mariath et al. 2019. PubMed ID: 31001817; Chen et al. 2020. PubMed ID: 32484238). This variant resides in exon 73 and results in a glycine amino acid substitution. Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) are predominant in autosomal dominant dystrophic epidermolysis bullosa (DDEB; https://www.ncbi.nlm.nih.gov/books/NBK1304/). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Recessive dystrophic epidermolysis bullosa;C0432322:Generalized dominant dystrophic epidermolysis bullosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 17, 2022

ACMG classification criteria: PS4 strong, PM1 moderate, PM2 moderate, PP1 strong, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Loss of glycosylation at K2038 (P = 0.0175);
MVP		0.99
MPC		0.30
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.95
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912844; hg19: chr3-48612852;