3-48575497-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000094.4(COL7A1):c.6022C>T(p.Arg2008Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,168 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2008H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

COL7A1
NM_000094.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.60

Publications

0 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 16 ACMG points.

PM1

In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000094.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-48575496-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1324153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 3-48575497-G-A is Pathogenic according to our data. Variant chr3-48575497-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522791.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.6022C>T	p.Arg2008Cys	missense_variant	Exon 74 of 119	ENST00000681320.1	NP_000085.1	Q02388-1Q59F16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL7A1	ENST00000681320.1 link	c.6022C>T	p.Arg2008Cys	missense_variant	Exon 74 of 119		NM_000094.4	ENSP00000506558.1	Q02388-1
COL7A1	ENST00000328333.12 link	c.6022C>T	p.Arg2008Cys	missense_variant	Exon 73 of 118	1		ENSP00000332371.8	Q02388-1
COL7A1	ENST00000487017.5 link	n.1939C>T		non_coding_transcript_exon_variant	Exon 39 of 83	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000409

AC:

AN:

244660

AF XY:

0.00

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:

0.00000916

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460168

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111764

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa

Pathogenic:5

Narges Medical Genetic and Prenatal Diagnosis Lab

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 14, 2022

Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 06, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 strong -

Nov 09, 2018

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PM2, PM5, PP2, PP3, PP5 -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.R2008C in COL7A1 (NM_000094.4) has been reported previously in affected indviduals (Escámez MJ et al,2018). It has been submitted to ClinVar as Pathogenic. Other variants affecting this residue have been reported previously. The p.R2008C variant is observed in 1/1,09,206 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R2008C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.6022 in COL7A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Epidermolysis bullosa dystrophica

Pathogenic:3

Mar 08, 2011

Biomedical Innovation Departament, CIEMAT

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 28, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Dec 14, 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 cysteine, which is neutral and slightly polar, at codon 2008 of the COL7A1 protein (p.Arg2008Cys). 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: 9740253, 10084325, 15888141, 16271705, 20184583). 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: 522791). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL7A1 protein function. This variant disrupts the p.Arg2008 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326325, 10084325, 10504458). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 11, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 10504458, 16271705, 15816848, 10367730, 27498345, 9740253, 34426522, 20184583, 31001817, 15888141, 10084325, 34008892, 35979658, 36578049, 36287101) -

Recessive dystrophic epidermolysis bullosa;C0268371:Dominant dystrophic epidermolysis bullosa with absence of skin;C0432321:Pretibial dystrophic epidermolysis bullosa;C0432322:Generalized dominant dystrophic epidermolysis bullosa;C1275114:Epidermolysis bullosa pruriginosa;C1843761:Nonsyndromic congenital nail disorder 8;C1851573:Transient bullous dermolysis of the newborn

Pathogenic:1

Mar 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.3

PhyloP100

2.6

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.61

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.89

MutPred

0.86

Loss of glycosylation at K2005 (P = 0.0028);

MVP

0.90

MPC

0.34

ClinPred

0.90

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.95

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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