10-104034271-CCAGGGGGTC-CG

Position:

• chr10-104034271-CCAGGGGGTC-CG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000494.4(COL17A1):​c.3821_3829delinsC​(p.Gly1274AlafsTer16) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL17A1 NM_000494.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.79

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]

ACMG classification

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 10-104034272-CAGGGGGTC-G is Pathogenic according to our data. Variant chr10-104034272-CAGGGGGTC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.3821_3829delinsC	p.Gly1274AlafsTer16	frameshift_variant	52/56	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.3821_3829delinsC	p.Gly1274AlafsTer16	frameshift_variant	52/56		NM_000494.4	ENSP00000497653	A2
COL17A1	ENST00000369733.8	c.3575_3583delinsC	p.Gly1192AlafsTer16	frameshift_variant	47/51	5		ENSP00000358748	P4

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change creates a premature translational stop signal (p.Gly1274Alafs*16) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL17A1-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Junctional epidermolysis bullosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 13, 2017

The p.Gly1274AlafsX16 (NM_000494.3 c.3821_3829delinsC) variant in COL17A1 has no t been previously reported in individuals with junctional epidermolysis bullosa. It has been identified in 1/94300 European chromosomes by the Genome Aggregatio n Database (http://gnomad.broadinstitute.org; referred to as p.Gly1274_Pro1276de l and p.Asp1278GlnfsTer14). This variant is predicted to cause a frameshift, whi ch alters the protein?s amino acid sequence beginning at position 1274 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of funct ion of the COL17A1 gene has been associated with junctional epidermolysis bullos a. In summary, although additional studies are required to fully establish its c linical significance, the p.Gly1274AlafsX16 variant is likely pathogenic for jun ctional epidermolysis bullosa in an autosomal recessive manner based on a predic ted variant effect. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1210666598; hg19: chr10-105794030;