rs797045084

Variant names:

• chr10-104043575-GACCCCTCTGAAA-G
• rs797045084
• NM_000494.4:c.2435-6_2440delTTTCAGAGGGGT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000494.4(COL17A1):​c.2435-6_2440delTTTCAGAGGGGT​(p.Glu812_Ser814delinsAla) variant causes a splice acceptor, disruptive inframe deletion, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL17A1 NM_000494.4 splice_acceptor, disruptive_inframe_deletion, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.97
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• epithelial recurrent erosion dystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• epidermolysis bullosa, junctional 4, intermediate

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• late-onset junctional epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• localized junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018024033 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 27, new splice context is: atcgatgctcactgtcccAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 10-104043575-GACCCCTCTGAAA-G is Pathogenic according to our data. Variant chr10-104043575-GACCCCTCTGAAA-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208569.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
COL17A1	NM_000494.4	c.2435-6_2440delTTTCAGAGGGGT	p.Glu812_Ser814delinsAla	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 35 of 56	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.2435-6_2440delTTTCAGAGGGGT	p.Glu812_Ser814delinsAla	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 35 of 56		NM_000494.4	ENSP00000497653.1
COL17A1	ENST00000369733.8	c.2435-6_2440delTTTCAGAGGGGT	p.Glu812_Ser814delinsAla	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 34 of 51	5		ENSP00000358748.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Pathogenic:1

Dec 18, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2435-6_2440del variant in COL17A1 has not been previously reported in individuals/any other families with disease. Data from large population studies is insufficient to assess the frequency of this variant. This variant deletes the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Homozygous or compound heterozygous loss of function variants in COL17A1 have been shown to cause junctional epidermolysis bullosa. In summary, although additional studies are required to fully establish its clinical significance, the c.2435-6_2440del variant is likely pathogenic. -

not provided Pathogenic:1

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the deletion of part of exon 35 (c.2435-6_2440del) of the COL17A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL17A1 are known to be pathogenic (PMID: 16473856, 17344927, 20301304, 21357940, 24319098). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL17A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 208569). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0

Splicing

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

Other links and lift over

dbSNP: rs797045084; hg19: chr10-105803333;