chr3-48575236-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP3_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 Likely 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

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

epidermolysis bullosa with congenital localized absence of skin and deformity of nails
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
dystrophic epidermolysis bullosa pruriginosa
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
recessive dystrophic epidermolysis bullosa
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, ClinGen
generalized dominant dystrophic epidermolysis bullosa
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
pretibial dystrophic epidermolysis bullosa
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
transient bullous dermolysis of the newborn
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
acral dystrophic epidermolysis bullosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dystrophic epidermolysis bullosa, nails only
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
recessive dystrophic epidermolysis bullosa inversa
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
recessive dystrophic epidermolysis bullosa-generalized other
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COL7A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000094.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-48575236-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1685282.Status of the report is criteria_provided_single_submitter, 1 stars.

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 VariationId is 17456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4 link	c.6187C>T	p.Arg2063Trp	missense_variant	Exon 75 of 119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL7A1	ENST00000681320.1 link	c.6187C>T	p.Arg2063Trp	missense_variant	Exon 75 of 119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12 link	c.6187C>T	p.Arg2063Trp	missense_variant	Exon 74 of 118	1		ENSP00000332371.8
COL7A1	ENST00000487017.5 link	n.2104C>T		non_coding_transcript_exon_variant	Exon 40 of 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

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251234

AF XY:

0.0000147

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 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

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Jul 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Pathogenic:2

Nov 02, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is present in population databases (rs121912849, gnomAD 0.002%). 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. ClinVar contains an entry for this variant (Variation ID: 17456). 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%. 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

Oct 31, 2017

Biomedical Innovation Departament, CIEMAT

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

(source)

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

PhyloP100

1.0

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

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over