Submissions for variant NM_000094.4(COL7A1):c.5819C>T (p.Pro1940Leu)

gnomAD frequency: 0.00098  dbSNP: rs149267939

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523251	SCV000616683	uncertain significance	not provided	2022-02-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16971478, 31001817, 34426522, 28523885, 32506467)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523251	SCV001066929	benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001148932	SCV001309853	uncertain significance	Epidermolysis bullosa dystrophica	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GenomeConnect, ClinGen	RCV000523251	SCV000986926	not provided	not provided		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 08/01/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV001275990	SCV001461692	benign	Epidermolysis bullosa dystrophica inversa, autosomal recessive	2020-01-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000523251	SCV001553193	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL7A1 p.Pro1940Leu variant was identified in two individuals with recessive dystrophic epidermolysis bullosa (Varki_2007_PMID:16971478; Heinecke_2017_PMID:28523885). The variant was identified in dbSNP (ID: rs149267939) and ClinVar (classified as uncertain significance by GeneDx and benign by Invitae). The variant was identified in control databases in 288 of 282184 chromosomes (1 homozygous) at a frequency of 0.001021 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 61 of 25098 chromosomes (freq: 0.00243), European (non-Finnish) in 180 of 128678 chromosomes (freq: 0.001399), Latino in 31 of 35412 chromosomes (freq: 0.000875), Other in 6 of 7206 chromosomes (freq: 0.000833), African in 8 of 24898 chromosomes (freq: 0.000321) and South Asian in 2 of 30608 chromosomes (freq: 0.000065), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Pro1940 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however this information is not predictive to rule out pathogenicity. The p.Pro1940Leu variant occurs in the second last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
PreventionGenetics, part of Exact Sciences	RCV003409742	SCV004114948	likely benign	COL7A1-related disorder	2023-12-26	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).