3-48575392-C-T

Position:

• chr3-48575392-C-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000094.4(COL7A1):​c.6127G>A​(p.Gly2043Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,936 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2043W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 21 ACMG points.

• PS1: Transcript NM_000094.4 (COL7A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL7A1. . Gene score misZ 1.5899 (greater than the threshold 3.09). Trascript score misZ 4.0428 (greater than threshold 3.09). GenCC has associacion of gene with recessive dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa pruriginosa, recessive dystrophic epidermolysis bullosa-generalized other, transient bullous dermolysis of the newborn, epidermolysis bullosa with congenital localized absence of skin and deformity of nails, generalized dominant dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa, nails only, acral dystrophic epidermolysis bullosa, recessive dystrophic epidermolysis bullosa inversa, pretibial dystrophic epidermolysis bullosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-48575392-C-T is Pathogenic according to our data. Variant chr3-48575392-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48575392-C-T is described in Lovd as [Pathogenic]. Variant chr3-48575392-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.6127G>A	p.Gly2043Arg	missense_variant	74/119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.6127G>A	p.Gly2043Arg	missense_variant	74/119		NM_000094.4	ENSP00000506558	P1
COL7A1	ENST00000328333.12	c.6127G>A	p.Gly2043Arg	missense_variant	73/118	1		ENSP00000332371	P1
COL7A1	ENST00000487017.5	n.2044G>A		non_coding_transcript_exon_variant	39/83	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458936 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 725718

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized dominant dystrophic epidermolysis bullosa Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires	Mar 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 26, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1998	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.G2043R in COL7A1 (NM_000094.4) is the most common recurrent variant in the autosomal dominant dystrophic epidermolysis bullosa (Christiano et al, Nishie et al,Vahidnezhad et al). It has been reported to ClinVar as Pathogenic.The p.G2043R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.G2043R missense variant is predicted to be damaging by both SIFT and PolyPhen2.The glycine residue at codon 2043 of COL7A1 is conserved in all mammalian species. The nucleotide c.6127 in COL7A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2021	One of the most common recurrent pathogenic variants identified in DDEB patients across all ethnic backgrounds (Nanda et al., 2018; Yenamandra et al., 2018; Chen et al., 2020); Published functional studies demonstrate a damaging effect, as G2043R induces intracytoplasmic accumulation of pro-C7, which hampers secretion of C7 in a dominant-negative fashion (Nishie et al., 2014); Located in the highly conserved Gly-X-Y repeat of the collagenous domain; Glycine substitution variants in this region of the COLVII protein destabilize the collagen triple helix resulting in skin fragility due to poor anchoring of the basement membrane to the underlying dermis (Pfendner and Lucky, 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24794830, 7861014, 28830826, 21448560, 9892921, 11260189, 9856843, 10951471, 32946877, 32506551, 31604626, 30011071, 29963685, 32484238, 9412818, 33274474) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 24, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL7A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and variants at these glycine residues in COL7A1 are more frequently observed in individuals with disease than in the general population (PMID: 22058051). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL7A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17438). This missense change has been observed in individual(s) with autosomal dominant dystrophic epidermolysis bullosa (PMID: 7861014). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2043 of the COL7A1 protein (p.Gly2043Arg). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Pretibial dystrophic epidermolysis bullosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 04, 2019

Variant summary: COL7A1 c.6127G>A (p.Gly2043Arg) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 243,072 control chromosomes (gnomAD). c.6127G>A has been reported in the literature in multiple individuals affected with Dominant Dystrophic Epidermolysis Bullosa (eg. Christiano_1995, Nishie_2014, Vahidnezhad_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant results in accumulation of collagen VII in the cytoplasm and increased susceptibility to enzymatic degradation (Nishie_2014). One other clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Epidermolysis bullosa dystrophica Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biomedical Innovation Departament, CIEMAT

Oct 19, 2018

- -

COL7A1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The COL7A1 c.6127G>A variant is predicted to result in the amino acid substitution p.Gly2043Arg. This variant has been previously reported in the heterozygous state in affected members of a family with autosomal dominant dystrophic epidermolysis bullosa (Christiano et al. 1995. PubMed ID: 7861014). It has also been reported as a recurrent de novo or inherited variant in many individuals with autosomal dominant dystrophic epidermolysis bullosa (Mellerio et al. 1998. PubMed ID: 9892921; Rouan et al. 1998. PubMed ID: 9856843; Wessagowit et al. 2001. PubMed ID: 11260189; Table S1, Almaani et al. 2011. PubMed ID: 21448560; Nishie et al. 2014. PubMed ID: 24794830; Supplementary Table S1, Vahidnezhad et al. 2017. PubMed ID: 28830826; Yenamandra et al. 2018. PubMed ID: 29963685; Nanda et al. 2018. PubMed ID: 30011071; Table S3, Chen et al. 2020. PubMed ID: 32484238). Furthermore, this variant resides in exon 73 and results in a glycine residue substitution. Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) are predominant in autosomal dominant dystrophic epidermolysis bullosa (DDEB; https://www.ncbi.nlm.nih.gov/books/NBK1304/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.94		Gain of MoRF binding (P = 0.0064);
MVP		0.95
MPC		0.30
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.95
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912836; hg19: chr3-48612825;