rs752317971

Positions:

Variant summary

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

The NM_000494.4(COL17A1):c.2407G>T(p.Gly803*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000434 in 1,614,070 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

COL17A1
NM_000494.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.49

Variant links:

Genes affected

COL17A1 (HGNC:2194): (collagen type XVII alpha 1 chain) This gene encodes the alpha chain of type XVII collagen. Unlike most collagens, collagen XVII is a transmembrane protein. Collagen XVII is a structural component of hemidesmosomes, multiprotein complexes at the dermal-epidermal basement membrane zone that mediate adhesion of keratinocytes to the underlying membrane. Mutations in this gene are associated with both generalized atrophic benign and junctional epidermolysis bullosa. Two homotrimeric forms of type XVII collagen exist. The full length form is the transmembrane protein. A soluble form, referred to as either ectodomain or LAD-1, is generated by proteolytic processing of the full length form. [provided by RefSeq, Jul 2008]

COL17A1 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 10-104043852-C-A is Pathogenic according to our data. Variant chr10-104043852-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 298713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104043852-C-A is described in Lovd as [Likely_pathogenic]. Variant chr10-104043852-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL17A1	NM_000494.4 linkuse as main transcript	c.2407G>T	p.Gly803*	stop_gained	34/56	ENST00000648076.2	NP_000485.3	Q9UMD9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2 linkuse as main transcript	c.2407G>T	p.Gly803*	stop_gained	34/56		NM_000494.4	ENSP00000497653.1		Q9UMD9-1
COL17A1	ENST00000369733.8 linkuse as main transcript	c.2407G>T	p.Gly803*	stop_gained	33/51	5		ENSP00000358748.3		Q9UMD9-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2023	Observed with a second COL17A1 variant on the opposite allele (in trans) in patients with epidermolysis bullosa referred for genetic testing at GeneDx and in published literature (Darling et al.,1997; Hoffmann et al., 2019); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12558632, 30673110, 9077475, 30761300, 21357940) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change creates a premature translational stop signal (p.Gly803*) in the COL17A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL17A1 are known to be pathogenic (PMID: 16473856, 17344927, 20301304, 21357940, 24319098). This variant is present in population databases (rs752317971, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 9077475). ClinVar contains an entry for this variant (Variation ID: 298713). 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. -

Junctional epidermolysis bullosa, non-Herlitz type

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The COL17A1 c.2407G>T (p.Gly803Ter) variant is a stop-gained variant predicted to result in premature truncation of the protein. The p.Gly803Ter variant has been reported in two studies in which it is found in a total of six patients with junctional epidermolysis bullosa, including in one in a homozygous state, in four in a compound heterozygous state, and in one in a heterozygous state in whom a second variant was not identified (Darling et al. 1997; Kiritsi et al. 2011). The variant was also detected in a heterozygous state in one unaffected father of one of the compound heterozygotes. The homozygous individual showed severely reduced staining for type XVII collagen in the skin. The p.Gly803Ter variant was absent from one control individual and is reported at a frequency of 0.00001 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Gly803Ter variant is classified as pathogenic for junctional epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Epidermolysis bullosa, junctional 4, intermediate

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.87

Vest4

0.74

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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