ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.5819C>T (p.Pro1940Leu) (rs149267939)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523251 SCV000616683 uncertain significance not provided 2017-07-14 criteria provided, single submitter clinical testing The P1940L variant in the COL7A1 gene has been reported previously in an individual with recessive dystrophic epidermolysis bullosa, but this individual also carried another variant on the same COL7A1 allele (in cis) in addition to a variant on the opposite COL7A1 allele (in trans) (Varki et al., 2007). The P1940L variant is observed in 13/6,508 (0.2%) and 85/65,910 (0.1%) alleles from individuals of Finnish and non-Finnish European background, respectively, in the ExAC dataset (Lek et al., 2016). The P1940L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P1940L as a variant of uncertain significance.
Invitae RCV000523251 SCV001066929 benign not provided 2020-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001148932 SCV001309853 uncertain significance Dystrophic epidermolysis bullosa 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.

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