rs1057517724

Variant names:

• chr3-48576771-C-G
• rs1057517724
• NM_000094.4:c.5605G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000094.4(COL7A1):​c.5605G>C​(p.Gly1869Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL7A1 NM_000094.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.21

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the COL7A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 223 curated pathogenic missense variants (we use a threshold of 10). The gene has 262 curated benign missense variants. Gene score misZ: 1.5899 (below the threshold of 3.09). Trascript score misZ: 4.0428 (above the threshold of 3.09). GenCC associations: The gene is linked to 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 3-48576771-C-G is Pathogenic according to our data. Variant chr3-48576771-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372341.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.5605G>C	p.Gly1869Arg	missense_variant, splice_region_variant	Exon 68 of 119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.5605G>C	p.Gly1869Arg	missense_variant, splice_region_variant	Exon 68 of 119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.5605G>C	p.Gly1869Arg	missense_variant, splice_region_variant	Exon 67 of 118	1		ENSP00000332371.8
COL7A1	ENST00000487017.5	n.1522G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 33 of 83	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726970

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa Pathogenic:1

Feb 13, 2018

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 27, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5605 G>C variant in the COL7A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant has been observed in the homozygous state in a patient referred for genetic testing for epidermolysis bullosa at GeneDx (parents not tested). The c.5605 G>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that c.5605 G>C may damage the splice acceptor site in intron 66, which may cause abnormal gene splicing. If c.5605 G>C does not alter splicing, it will result in the G1869R missense change. The G1869R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, affecting a Glycine residue of the triple-helical region containing Gly-X-Y repeats. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.5605 G>C as a pathogenic variant. -

COL7A1-related disorder Pathogenic:1

Feb 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL7A1 c.5605G>C variant is predicted to result in the amino acid substitution p.Gly1869Arg. This variant has been reported in the compound heterozygous state in an individual with dystrophic epidermolysis bullosa (Table S5, Chen et al. 2023. PubMed ID: 36287101). The amino acid residue p.Gly1869 resides within the triple helical domain of the COL7A1 protein (amino acids 1254-2783). Glycine substitutions within this domain affect the folding and secretion of type VII collagen, and pathogenic variants altering glycine residues have been reported in individuals with COL7A1-related disorders (Dang and Murrell. 2008. PubMed ID: 18558993; Abu Sa'd et al. 2006. PubMed ID: 16439963; Almaani et al. 2011. PubMed ID: 21448560; Vahidnezhad et al. 2017. PubMed ID: 27899325). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

not specified Uncertain:1

Dec 16, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL7A1 c.5605G>C (p.Gly1869Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248914 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5605G>C has been reported in the literature in at least one individual affected with Dystrophic Epidermolysis Bullosa, Recessive (Chen_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36287101). ClinVar contains an entry for this variant (Variation ID: 372341). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.92		Gain of glycosylation at S1865 (P = 0.0015);
MVP		0.94
MPC		0.30
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.46
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: 29

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057517724; hg19: chr3-48614204;