Submissions for variant NM_000094.4(COL7A1):c.4559C>T (p.Pro1520Leu)

gnomAD frequency: 0.00113  dbSNP: rs140114392

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000922787	SCV001068230	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001150557	SCV001311635	likely benign	Epidermolysis bullosa dystrophica	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000922787	SCV004154483	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	COL7A1: BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000922787	SCV005261349	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000922787	SCV001551847	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL7A1 p.Pro1520Leu variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs140114392) and in control databases in 130 of 282088 chromosomes (1 homozygous) at a frequency of 0.0004608 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: African in 106 of 24878 chromosomes (freq: 0.004261), Other in 5 of 7204 chromosomes (freq: 0.000694), Latino in 7 of 35420 chromosomes (freq: 0.000198), European (non-Finnish) in 10 of 128598 chromosomes (freq: 0.000078) and South Asian in 2 of 30588 chromosomes (freq: 0.000065), but was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Pro1520 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Natera, Inc.	RCV001150557	SCV002079246	benign	Epidermolysis bullosa dystrophica	2020-05-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003970501	SCV004779958	likely benign	COL7A1-related disorder	2022-12-10	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).