rs121912849

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000094.4(COL7A1):c.6187C>T(p.Arg2063Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,812 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. R2063G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

COL7A1
NM_000094.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.01

Variant links:

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]

COL7A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a compositionally_biased_region Basic and acidic residues (size 17) in uniprot entity CO7A1_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000094.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-48575236-G-C is described in Lovd as [Pathogenic].

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, 0.889

PP5

Variant 3-48575236-G-A is Pathogenic according to our data. Variant chr3-48575236-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48575236-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL7A1	NM_000094.4 linkuse as main transcript	c.6187C>T	p.Arg2063Trp	missense_variant	75/119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1 linkuse as main transcript	c.6187C>T	p.Arg2063Trp	missense_variant	75/119		NM_000094.4	ENSP00000506558	P1	Q02388-1
COL7A1	ENST00000328333.12 linkuse as main transcript	c.6187C>T	p.Arg2063Trp	missense_variant	74/118	1		ENSP00000332371	P1	Q02388-1
COL7A1	ENST00000487017.5 linkuse as main transcript	n.2104C>T		non_coding_transcript_exon_variant	40/83	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251234

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461696

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R2063W in COL7A1 (NM_000094.3) has been previously reported in affected patients (Ben Brick et al., 2014).Functional studies have demonstrated a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.R2063W variant is observed in 2/1,13,580 (0.0018%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2024	Variant summary: COL7A1 c.6187C>T (p.Arg2063Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251234 control chromosomes. c.6187C>T has been reported in the literature in the presumed compound heterozygous, compound heterozygous, or homozygous state in multiple individuals affected with autosomal recessive Dystrophic Epidermolysis Bullosa (example, Ben Brick_2014, Chen_2023, Hovanian_1997, Jerabkova_2010), including in at least 1 individual who carried a pathogenic variant in trans. Additionally, this variant was found in the heterozygous state in several individuals affected with dystrophic epidermolysis bullosa (example, Ben Brick_2014, Cuadro-Corrales_2010, Danescu_2015, Escamez_2010, Posteraro_2005), however parental genotype/phenotype correlations were not available. These data indicate that the variant is very likely to be associated with disease. In homozygous patient samples, this variant was associated with normal transcription and protein expression levels in at least 1 study (example, Hovanian_1997), however follow up studies in patient samples heterozygous for this variant found that collagen VII protein levels were reduced and altered (data not quantified) (example, Escamez_2010, Posteraro_2005). In vitro, this variant resulted in reduced fibroblast adhesion and keratinocyte migration, as well as increased susceptibility to protease digestion (example, Woodley_2008, Woodley_2021). The following publications have been ascertained in the context of this evaluation (PMID: 24170138, 36287101, 20920254, 25201089, 20184583, 9326325, 20598510, 16271705, 27899325, 18450758, 34674926). ClinVar contains an entry for this variant (Variation ID: 17456). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2022	Reported previously in the homozygous state or with a second COL7A1 variant in patients with autosomal recessive DEB (Hovnanian et al., 1997; Hashimoto et al., 1999; Gardella et al., 2002; Kern et al., 2009; Ben Brick et al., 2014; Kopeckova et al., 2016; Chen et al., 2020); Identified in unrelated patients with generalized DEB as a single heterozygous variant with no second COL7A1 variant identified (Posteraro et al., 2005; Escamez et al., 2010; Ben Brick et al., 2014; Danescu et al., 2015); Published functional studies demonstrate that this variant is located next to the helical interruption hinge region and results in local triple helix destabilization, and fibroblasts with this variant exhibit decreased motility and adhesion in vitro (Woodley et al., 2006); 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: 20184583, 33969388, 21448560, 12207583, 19681861, 10232406, 18558993, 16271705, 12880418, 25201089, 15115517, 18030675, 26707537, 28830826, 34426522, 24170138, 35314946, 32484238, 9326325, 18450758) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2023	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. ClinVar contains an entry for this variant (Variation ID: 17456). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 9326325, 12207583, 28830826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121912849, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2063 of the COL7A1 protein (p.Arg2063Trp). Experimental studies have shown that this missense change affects COL7A1 function (PMID: 18450758). For these reasons, this variant has been classified as Pathogenic. -

Epidermolysis bullosa dystrophica

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biomedical Innovation Departament, CIEMAT

Oct 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.85

Eigen

Benign

-0.087

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

0.11

A;A

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.65

Sift

Benign

0.045

Sift4G

Uncertain

0.0040

Polyphen

0.67

Vest4

0.59

MutPred

0.52

Loss of glycosylation at K2066 (P = 0.0018);

MVP

0.90

MPC

0.26

ClinPred

0.90

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.31

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over