rs121912838

Positions:

chr3-48575428-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP2PP3_StrongPP5

The NM_000094.4(COL7A1):c.6091G>A(p.Gly2031Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,700 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

COL7A1
NM_000094.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 7.55

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

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, 0.989

PP5

Variant 3-48575428-C-T is Pathogenic according to our data. Variant chr3-48575428-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17446.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL7A1	NM_000094.4 linkuse as main transcript	c.6091G>A	p.Gly2031Ser	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 linkuse as main transcript	c.6091G>A	p.Gly2031Ser	missense_variant	74/119		NM_000094.4	ENSP00000506558	P1	Q02388-1
COL7A1	ENST00000328333.12 linkuse as main transcript	c.6091G>A	p.Gly2031Ser	missense_variant	73/118	1		ENSP00000332371	P1	Q02388-1
COL7A1	ENST00000487017.5 linkuse as main transcript	n.2008G>A		non_coding_transcript_exon_variant	39/83	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000253

AC:

AN:

237354

Hom.:

AF XY:

0.0000307

AC XY:

AN XY:

130280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000619

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1457548

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

725054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000461

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2022	Identified in multiple unrelated patients referred for genetic testing at GeneDx and in the published literature, with either an autosomal dominant or autosomal recessive inheritance pattern, sometimes presenting with different inheritance patterns in members of the same family (Almaani et al., 2011; Hamidi et al., 2016; E Pfendner, unpublished); 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); 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: 34435747, 21448560, 11167698, 27746867, 31216405, 30924923) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2031 of the COL7A1 protein (p.Gly2031Ser). This variant is present in population databases (rs121912838, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive epidermolysis bullosa (PMID: 11167698, 27746867). ClinVar contains an entry for this variant (Variation ID: 17446). 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 with a positive predictive value of 95%. 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. For these reasons, this variant has been classified as Pathogenic. -

Epidermolysis bullosa dystrophica

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 10, 2020

- -

Recessive dystrophic epidermolysis bullosa;C0268371:Dominant dystrophic epidermolysis bullosa with absence of skin;C0432321:Pretibial dystrophic epidermolysis bullosa;C0432322:Generalized dominant dystrophic epidermolysis bullosa;C1275114:Epidermolysis bullosa pruriginosa;C1843761:Nonsyndromic congenital nail disorder 8;C1851573:Transient bullous dermolysis of the newborn

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 20, 2012

- -

Duane retraction syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Feb 26, 2024

The heterozygous p.Gly2031Ser variant in COL7A1 was identified in 1 individual with Duane Retraction Syndrome (DRS), hand and finger anomalies, and absent nails via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). While this gene has a definitive gene-disease association with autosomal dominant or recessive dystrophic epidermolysis bullosa and an autosomal dominant nail disorder, it is lacking sufficient evidence to establish a gene-disease relationship for DRS. An additional variant (p.Arg894Cys) in KIF5C was also detected in heterozygosity with this variant. While these genes are lacking sufficient evidence, we believe that both variants may be contributing to the phenotype. Given the limited information about this gene-disease relationship, the significance of the p.Gly2031Ser variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in COL7A1 we encourage you to reach out to the Engle Lab (elizabeth.engle@childrens.harvard.edu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.97

MutPred

0.91

Loss of glycosylation at P2027 (P = 0.0203);

MVP

0.98

MPC

0.25

ClinPred

0.97

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.67

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over