rs144023803

Positions:

chr3-48590721-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000094.4(COL7A1):c.1732C>T(p.Arg578Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000116 in 1,613,898 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

COL7A1
NM_000094.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 5.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

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

PP5

Variant 3-48590721-G-A is Pathogenic according to our data. Variant chr3-48590721-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 372330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48590721-G-A is described in Lovd as [Pathogenic]. Variant chr3-48590721-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4 linkuse as main transcript	c.1732C>T	p.Arg578Ter	stop_gained	14/119	ENST00000681320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1 linkuse as main transcript	c.1732C>T	p.Arg578Ter	stop_gained	14/119		NM_000094.4	P1	Q02388-1
COL7A1	ENST00000328333.12 linkuse as main transcript	c.1732C>T	p.Arg578Ter	stop_gained	13/118	1		P1	Q02388-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251302

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461716

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000160

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000353

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 30, 2017	The NM_000094.3(COL7A1):c.1732C>T heterozygous nonsense variant was identified in exon 13 of COL7A1. This nonsense variant creates a stop codon at amino acid position 578, NP_000085.1(COL7A1):p.(Arg578*). This is predicted to result in loss of protein function either through truncation (~75% of the protein, including multiple triple helix repeats) or nonsense-mediated decay. This variant is present in the gnomAD population database at a frequency of 0.004%. It has been previously reported in multiple families with recessive dystrophic epidermolysis bullosa in homozygous or compound heterozygous state (Dunnill et al., (1994), Whittock et al., (1999) and Kern et al., (2006)). In addition, other truncating variants downstream of c.1732C>T in the COL7A1 gene have been reported as pathogenic in individuals with this condition (ClinVar). Based on current information and in association with the NM_000094.3(COL7A1):c.3265C>T nonsense variant, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained c.1732C>T p.Arg578Ter variant in COL7A1 gene has been previously reported in homozygous, heterozygous and compound heterozygous states in multiple individuals affected with Epidermolysis bullosa dystrophica Whittock et al., 1999; Alamani et al., 2010; Serafi et al., 2015. The p.Arg578Ter variant has been reported to segregated with disease Serafi et al., 2015. The p.Arg578Ter variant is reported with allele frequency of 0.03% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The nucleotide change c.1732C>T in COL7A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal p.Arg578Ter in the COL7A1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in COL7A1 gene have been previously reported to be pathogenic Varki et al., 2007. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21448560, 28549954, 25525159, 26102279, 7833933, 10504458, 14727126, 28168442, 20357813, 28691931, 29625052, 26689913, 33274474) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Arg578*) 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 present in population databases (rs144023803, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 17425959, 26102279). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372330). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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

Feb 26, 2022

- -

Epidermolysis bullosa dystrophica

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 22, 2018

The COL7A1 c.1732C>T (p.Arg578Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, The p.Arg578Ter variant has been found in at least 21 individuals with dystrophic epidermolysis bullosa, including in four in a homozygous state, in at least 15 in a compound heterozygous state, and in at least two in a heterozygous state (Dunnill et al. 1994; Hovnanian et al. 1997; Mellerio et al. 1997; Whittock et al. 1999; Almaani et al. 2010; Nagy et al. 2011; Petrof et al. 2013; Takeichi et al. 2015; Serafi et al. 2015; Georgiadis et al. 2016). Three of the studies demonstrated that the p.Arg578Ter variant segregated with disease (Dunnill et al. 1994; Mellerio et al. 1997; Serafi et al. 2015). The p.Arg578Ter variant was absent from 180 control chromosomes and is reported at a frequency of 0.000089 in the Latino population of the Genome Aggregation Database. The p.Arg578Ter variant is predicted to result in premature termination and the loss of approximately 80% of the protein. Due to the potential impact of stop-gained variants and available evidence, the p.Arg578Ter 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. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 08, 2021

ACMG categories: PVS1,PM2,PP3,PP5 -

Generalized dominant dystrophic epidermolysis bullosa

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

A;A

Vest4

0.85

GERP RS

5.0

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