rs121912836

Variant names:

• chr3-48575392-C-A
• rs121912836
• NM_000094.4:c.6127G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-48575392-C-A
• chr3-48575392-C-G
• chr3-48575392-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000094.4(COL7A1):​c.6127G>T​(p.Gly2043Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2043E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.97
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• epidermolysis bullosa with congenital localized absence of skin and deformity of nails

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dystrophic epidermolysis bullosa pruriginosa

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• recessive dystrophic epidermolysis bullosa

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, ClinGen
• generalized dominant dystrophic epidermolysis bullosa

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• pretibial dystrophic epidermolysis bullosa

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• transient bullous dermolysis of the newborn

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• acral dystrophic epidermolysis bullosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dystrophic epidermolysis bullosa, nails only

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• recessive dystrophic epidermolysis bullosa inversa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive dystrophic epidermolysis bullosa-generalized other

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000094.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-48575391-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1695074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-48575392-C-A is Pathogenic according to our data. Variant chr3-48575392-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 419628.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000094.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL7A1	NM_000094.4	MANE Select	c.6127G>T	p.Gly2043Trp	missense	Exon 74 of 119	NP_000085.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL7A1	ENST00000681320.1	MANE Select	c.6127G>T	p.Gly2043Trp	missense	Exon 74 of 119	ENSP00000506558.1
	COL7A1	ENST00000328333.12	TSL:1	c.6127G>T	p.Gly2043Trp	missense	Exon 73 of 118	ENSP00000332371.8
	COL7A1	ENST00000487017.5	TSL:5	n.2044G>T		non_coding_transcript_exon	Exon 39 of 83

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 22, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G2043W substitution in the COL7A1 gene has been reported previously as a pathogenic variantand is the same position as the most common recurrent autosomal dominant COL7A1 variant (G2043R)in DDEB patients (Varki et al 2006). The p.G2043W variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The p.G2043W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this substitution is probably damaging to the protein structure/function as it occurs at the first Glycine position of the canonical Gly-X-Y repeat in the collagenous domain of the COLVII protein. Glycine substitution variants in this region of the collagen VII protein will destabilize the collagen triplehelix resulting in anchoring fibrils that are unstable and result in poor anchoring off the basementmembrane to the underlying dermis. Missense variants at the same residue (G2043R, G2043E) andnearby residues (G2031S, G2037R) have been reported in the Human Gene Mutation Database inassociation with DEB (Stenson et al., 2009), supporting the functional importance of this region of theprotein. We interpret G2043W in COL7A1 as a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		6.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.93		Loss of glycosylation at K2038 (P = 0.0175)
MVP		0.92
MPC		0.29
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.95
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912836; hg19: chr3-48612825;