chr3-48576272-G-A

Position:

chr3-48576272-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000094.4(COL7A1):c.5797C>T(p.Arg1933*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,666 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COL7A1
NM_000094.4 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.166

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:

COL7A1 (HGNC:):

COL7A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-48576272-G-A is Pathogenic according to our data. Variant chr3-48576272-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 345830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48576272-G-A is described in Lovd as [Pathogenic]. Variant chr3-48576272-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.5797C>T	p.Arg1933*	stop_gained	71/119	ENST00000681320.1	NP_000085.1	Q02388-1Q59F16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL7A1	ENST00000681320.1 linkuse as main transcript	c.5797C>T	p.Arg1933*	stop_gained	71/119		NM_000094.4	ENSP00000506558.1	Q02388-1
COL7A1	ENST00000328333.12 linkuse as main transcript	c.5797C>T	p.Arg1933*	stop_gained	70/118	1		ENSP00000332371.8	Q02388-1
COL7A1	ENST00000487017.5 linkuse as main transcript	n.1714C>T		non_coding_transcript_exon_variant	36/83	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461546

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727058

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000495

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa

Pathogenic:2

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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with dystrophic epidermolysis bullosa (DEB) (OMIM, PMID: 31670143). (I) 0108 - This gene is associated with both recessive and dominant disease. The spectrum of DEB associated with this gene can be either dominant or recessive. Dominant inheritance (DDEB; MIM#131750) is typically associated with milder phenotypes, whereas recessive inheritance (RDEB; MIM#226600) is usually observed in more severe cases (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity ranges from involving only nails to generalised and severe blistering and scarring (PMID: 31670143). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple unrelated individuals with recessived dystrophic epidermolysis bullosa (PMID: 16484981). It has also been reported multiple times as pathogenic in ClinVar. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000094.3(COL7A1):c.497dup; p.(Val168Glyfs*12)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis performed by Fulgent laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Epidermolysis bullosa dystrophica

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The COL7A1 c.5797C>T (p.Arg1933Ter) variant is a stop-gained variant reported in a total of ten individuals with dystrophic epidermolysis bullosa, including one homozygote, seven compound heterozygotes, two affected heterozygotes in whom a second variant was not identified, and in one unaffected heterozygous parent of an affected individual (Whittock et al. 1999; Csikos et al. 2003; Wessagowit et al. 2005; Kern et al. 2006; Arnold et al. 2009; Escamez et al. 2010; Montaudie et al. 2016). The variant was absent from 100 control individuals and from 192 control chromosomes (Csikos et al. 2005; Oh et al. 2007; Escamez et al. 2010). It is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on only one allele in a region of good sequence coverage, so it is presumed to be rare. Expression studies in HEK293 cells showed a complete lack of expression of the p.Arg1933Ter variant (Cogan et al. 2014). Based on the evidence, the p.Arg1933Ter 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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2023

This sequence change creates a premature translational stop signal (p.Arg1933*) in the COL7A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive epidermolysis bullosa dystrophica (PMID: 10504458, 12653705, 15816848, 27544590, 29500833). ClinVar contains an entry for this variant (Variation ID: 345830). For these reasons, this variant has been classified as Pathogenic. -

Epidermolysis bullosa dystrophica inversa, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

COL7A1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 13, 2023

Variant summary: COL7A1 c.5797C>T (p.Arg1933X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and reported in association with Epidermolysis bullosa dystrophica in HGMD. The variant was absent in 250778 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5797C>T has been reported in the literature in both compound heterozygous and homozygous individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (e.g., Whittock_1999, Kern_2006). These data indicate that the variant is likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Benign

-0.086

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.14

Vest4

0.84

GERP RS

-0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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