NM_000494.4:c.3908G>A

Variant names:

• chr10-104034193-C-T
• rs121912771
• NM_000494.4:c.3908G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NM_000494.4(COL17A1):​c.3908G>A​(p.Arg1303Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,258 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002525415: Published functional studies demonstrate a damaging effect of the R1303Q variant on keratinocyte adhesion and collagen XVII-laminin interactions (Kroeger et al., 2019)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1303R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.491
• Publications: 15 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermolysis bullosa, junctional 4, intermediate

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002525415: Published functional studies demonstrate a damaging effect of the R1303Q variant on keratinocyte adhesion and collagen XVII-laminin interactions (Kroeger et al., 2019); PMID:31589614, 26604146, 9199555, 17263807, 21466533, 33393081, 23550562, 24005051, 30316981; SCV005353094: "In vitro functional studies using patient keratinocytes demonstrated this variant resides in the laminin-332 binding site and results in diminished cell adhesion and impaired migration (Kroeger et al. 2018. PubMed ID: 30316981)."
• PP5: Variant 10-104034193-C-T is Pathogenic according to our data. Variant chr10-104034193-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000494.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	NM_000494.4	MANE Select	c.3908G>A	p.Arg1303Gln	missense	Exon 52 of 56	NP_000485.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	ENST00000648076.2	MANE Select	c.3908G>A	p.Arg1303Gln	missense	Exon 52 of 56	ENSP00000497653.1	Q9UMD9-1
	COL17A1	ENST00000859462.1		c.3908G>A	p.Arg1303Gln	missense	Exon 52 of 56	ENSP00000529521.1
	COL17A1	ENST00000859464.1		c.3905G>A	p.Arg1302Gln	missense	Exon 52 of 56	ENSP00000529523.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 249846 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 175 AN: 1460940 Hom.: 1 Cov.: 33 AF XY: 0.000118 AC XY: 86 AN XY: 726748

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86168

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5360

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111900

Other (OTH) AF: 0.0000332 AC: 2 AN: 60306

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74478

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000167 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
1	-	-	COL17A1-related disorder (1)
1	-	-	Epidermolysis bullosa, junctional 4, intermediate (1)
1	-	-	Epithelial recurrent erosion dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Benign	0.82
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.49
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.55
Sift	Benign	0.49	T
Sift4G	Benign	0.33	T
Polyphen		0.71	P
Vest4		0.27
MVP		0.67
MPC		0.075
ClinPred		0.065	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.30
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 2

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

Other links and lift over

dbSNP: rs121912771; hg19: chr10-105793951; COSMIC: COSV100212230; COSMIC: COSV100212230;