ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.1613G>A (p.Arg538His) (rs138791004)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000268243 SCV000445141 uncertain significance Dystrophic epidermolysis bullosa 2018-01-12 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000894599 SCV001038594 likely benign not provided 2020-12-06 criteria provided, single submitter clinical testing
Natera, Inc. RCV000268243 SCV001456759 uncertain significance Dystrophic epidermolysis bullosa 2019-10-28 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000894599 SCV001550594 uncertain significance not provided no assertion criteria provided clinical testing The COL7A1 p.Arg538His variant was identified in 7 of 3352 proband chromosomes (freq: 0.002) from individuals with Age-related Macular Degeneration and 2 of 1490 contorl chromosomes (freq: 0.001) (Seddon_2013_PMID:24036952). The variant was also identified in dbSNP (ID: rs138791004), ClinVar (classified as a VUS by Illumina) and Cosmic (found somatically in kidney tumour tissue). The variant was identified in control databases in 410 of 282430 chromosomes at a frequency of 0.001452 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 330 of 128948 chromosomes (freq: 0.002559), Other in 9 of 7212 chromosomes (freq: 0.001248), South Asian in 35 of 30604 chromosomes (freq: 0.001144), Ashkenazi Jewish in 9 of 10338 chromosomes (freq: 0.000871), African in 11 of 24922 chromosomes (freq: 0.000441), European (Finnish) in 7 of 25048 chromosomes (freq: 0.00028) and Latino in 9 of 35410 chromosomes (freq: 0.000254); it was not observed in the East Asian population. The p.Arg538His residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. This variant is classified as a variant of uncertain significance.

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