rs121912856

Variant names:

• chr3-48593538-T-C
• rs121912856
• NM_000094.4:c.425A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

The NM_000094.4(COL7A1):​c.425A>G​(p.Lys142Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000458 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: COL7A1 NM_000094.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 5.69
• Publications: 50 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000094.4
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-48593538-T-C is Pathogenic according to our data. Variant chr3-48593538-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 29636.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	c.425A>G	p.Lys142Arg	missense_variant, splice_region_variant	Exon 4 of 119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.425A>G	p.Lys142Arg	missense_variant, splice_region_variant	Exon 4 of 119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.425A>G	p.Lys142Arg	missense_variant, splice_region_variant	Exon 3 of 118	1		ENSP00000332371.8

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251394 AF XY: 0.0000368

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: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.0000481 AC XY: 35 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000835 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa Pathogenic:4

Nov 09, 2018

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2016

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

Jul 09, 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.425A>G (p.Lys142Arg) results in a conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site and three predict the variant also creates a 3' acceptor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing, resulting in the creation of a premature termination codon (e.g. Gardella_1996). The variant allele was found at a frequency of 3.2e-05 in 251394 control chromosomes. c.425A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Recessive Dystrophic Epidermolysis Bullosa (eg. Gardella_1996, Jerabkova_2010). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8755915, 20598510). ClinVar contains an entry for this variant (Variation ID: 29636). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 142 of the COL7A1 protein (p.Lys142Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs121912856, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive epidermolysis bullosa dystrophica (PMID: 11781296, 12787275, 15888141, 16971478, 19681861, 22266148). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29636). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Studies have shown that this missense change results in abnormal splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 8755915, 10408773). For these reasons, this variant has been classified as Pathogenic. -

Feb 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant predicted to damage or destroy the natural splice donor site for intron 3 and demonstrated to result in loss-of-function through cDNA analysis of cultured skin fibroblasts from a patient with c.425 A>G (Gardella et al., 1996); This variant is associated with the following publications: (PMID: 15888141, 12485454, 11781296, 8755915, 12787275, 22266148, 29080321, 26990548, 21448560, 34008892, 31589614, 16971478, 34426522, 33274474) -

Epidermolysis bullosa dystrophica Pathogenic:3

Jan 26, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys142Arg variant in COL7A1 has been reported in the homozygous or compoun d heterozygous state in >15 individuals with dystrophic epidermolysis bullosa ( DEB) (Gardella 1996, Gardella 2002, Csikos 2005). This variant has also been ide ntified in 0.01% (12/126664) of European chromosomes by the Genome Aggregation D atabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121912856). Although this variant has been seen in the general population, its frequency is low enoug h to be consistent with a recessive carrier frequency. This variant is located w ithin the last three bases of exon 3, which is part of the 5' splice region. Com putational tools do suggest an impact to splicing, and functional studies have s hown that this variant impacts splicing of exon 3, leading to a truncated or abs ent protein (Gardella 1996). Loss of function of the COL7A1 gene is an establish ed disease mechanism in autosomal recessive DEB. In summary, this variant meets criteria to be classified as pathogenic for DEB in an autosomal recessive manner . ACMG/AMP Criteria applied: PM3_Very Strong; PS3; PP3; PP4. -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in COL7A1 is predicted to replace lysine with arginine at codon 142, p.(Lys142Arg). This variant also falls at the second last nucleotide of exon 3 of the COL7A1 coding sequence, which is part of the consensus donor splice site for this exon. The highest population minor allele frequency in gnomAD v2.1 is 0.007% (9/129,144 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been detected in at least 12 individuals with recessive dystrophic epidermolysis bullosa (RDEB). Of those individuals, two individuals were homozygous and 10 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed in trans by parental testing. All these cases demonstrated loss or reduced expression of Collagen VII in the dermal-epidermal junction (PMID: 8755915, 10408773, 12787275, 15888141). The variant has been reported to segregate with RDEB in at least one family (PMID: 12787275). Multiple lines of computational evidence predict an impact on splicing (SpliceAI, MaxEntScan, NNSplice), and have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). The splicing prediction is confirmed by RT-PCR and allele-specific analyses in skin fibroblasts. The assay demonstrated that the variant impacts splicing by full expression of three aberrant transcripts (all expected to undergo nonsense-mediated decay), exon 3 skipping being the most prevalent (PMID: 8755915, 10408773). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PM3_VeryStrong, PM2_Supporting, PP1, PP3, PP4. -

Oct 11, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the COL7A1 c.425A>G (p.Lys142Arg) missense variant has been identified in 42 individuals with dystrophic epidermolysis bullosa, including in a homozygous state in nine probands, in a compound heterozygous state in 30 probands, and in a heterozygous state in 3 probands with second alleles not identified (Gardella et al. 1996; Csikos et al. 2005; Jerabkova et al. 2010; Wertheim-Tysarowska et al. 2012). The p.Lys142Arg variant was found in a heterozygous state in one of 100 control alleles (Csikos et al. 2005) and is reported at a frequency of 0.000095 in the European (non-Finnish) population of the Genome Aggregation Database. RT-PCR found the p.Lys142Arg variant to have aberrant transcripts that indicate exon skipping (Gardella et al. 1996). Based on the evidence, the p.Lys142Arg variant is classified as pathogenic for dystrophic epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Epidermolysis bullosa dystrophica inversa, autosomal recessive Pathogenic:2

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jun 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epidermolysis bullosa pruriginosa, autosomal recessive Pathogenic:1

Oct 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Epidermolysis bullosa pruriginosa Pathogenic:1

Feb 26, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3,PP4. This variant was detected in homozygous state. -

Anonychia Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL7A1-related disorder Pathogenic:1

May 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL7A1 c.425A>G variant is predicted to result in the amino acid substitution p.Lys142Arg. This variant has been frequently reported in the homozygous or compound heterozygous state in individuals with epidermolysis bullosa dystrophica (see for example Rossi et al. 2021. PubMed ID: 33274474; Zimmer et al. 2002. PubMed ID: 11781296; Table SII in Almaani et al. 2011. PubMed ID: 21448560; Kahofer et al. 2003. PubMed ID: 12787275; Drera et al. 2006. PubMed ID: 16965329; Gardella et al. 2002. PubMed ID: 12485454; Varki et al. 2007. PubMed ID: 16971478); and, it has been shown to disrupt the canonical splice donor site (Gardella et al. 1999. PubMed ID: 10408773). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Nail dystrophy;C3887524:Skin erosion;C5848159:Abnormality of the skin Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epidermolysis bullosa dystrophica, autosomal recessive, localisata variant Pathogenic:1

Oct 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.7
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.56
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.95
MPC		0.20
ClinPred		0.18	T
GERP RS		4.2
Varity_R		0.19
gMVP		0.73
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.65		Position offset: -1

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

Other links and lift over

dbSNP: rs121912856; hg19: chr3-48630971;