Submissions for variant NM_000094.4(COL7A1):c.5096C>T (p.Pro1699Leu)

gnomAD frequency: 0.00001  dbSNP: rs121912845

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biomedical Innovation Departament, CIEMAT	RCV001352849	SCV001547315	pathogenic	Epidermolysis bullosa dystrophica	2018-03-26	criteria provided, single submitter	research
Invitae	RCV001355300	SCV003525162	likely pathogenic	not provided	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1699 of the COL7A1 protein (p.Pro1699Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive COL7A1-related conditions (PMID: 12485454, 26864810). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17451). 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 not expected to disrupt COL7A1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM	RCV000019002	SCV000039289	pathogenic	Epidermolysis bullosa, pretibial, autosomal recessive	2002-12-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355300	SCV001550150	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL7A1 p.P1699L variant was identified in the literature in a compound heterozygous individual with Dystrophic Epidermolysis Bullosa and a compound heterozygous individual with Aplasia Cutis Congenita in Bullous Dermolysis Gardella_2002_PMID:12485454; Diociaiuti_2016_PMID:26864810). The variant was identified in dbSNP (ID: rs121912845) and ClinVar (classified as pathogenic by OMIM). The variant was identified in control databases in 6 of 273692 chromosomes at a frequency of 0.00002192 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.P1699 residue is conserved in mammals and computational analyses (MUT Assesor, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.