rs121912856

chr3-48593538-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2 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. 2/2 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:18
• Conservation: PhyloP100: 5.69

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 11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL7A1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. 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 id is 29636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48593538-T-C is described in Lovd as [Pathogenic]. Variant chr3-48593538-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4	c.425A>G	p.Lys142Arg	missense_variant, splice_region_variant	4/119	ENST00000681320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1	c.425A>G	p.Lys142Arg	missense_variant, splice_region_variant	4/119		NM_000094.4	P1
COL7A1	ENST00000328333.12	c.425A>G	p.Lys142Arg	missense_variant, splice_region_variant	3/118	1		P1

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

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251394 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135862

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: 0.0000616

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

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: 0.0000540

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000853 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:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

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	Invitae	Dec 19, 2023	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 disrupted 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 introduces a premature termination codon (PMID: 8755915, 10408773). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2022	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

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 11, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	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. -

Recessive dystrophic epidermolysis bullosa Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires	Mar 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Jun 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Nov 09, 2018	- -

Epidermolysis bullosa dystrophica inversa, autosomal recessive Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Epidermolysis bullosa pruriginosa, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2006

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 03, 2021

- -

Abnormality of the skin;C0221260:Nail dystrophy;C3887524:Skin erosion Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Epidermolysis bullosa pruriginosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 26, 2019

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2006

- -

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
MutationTaster	Benign	0.99	A;A
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912856; hg19: chr3-48630971;