ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.3829G>A (rs190598500)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671820 SCV000796842 uncertain significance Alport syndrome, autosomal recessive 2018-01-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727653 SCV000854957 likely pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001143340 SCV001303860 uncertain significance Alport syndrome 2017-04-28 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Biology Laboratory, Fundació Puigvert RCV001281229 SCV001425004 uncertain significance Alport syndrome 3, autosomal dominant 2021-05-31 criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000727653 SCV001554089 uncertain significance not provided no assertion criteria provided clinical testing The COL4A3 p.Gly1277Ser variant was identified in 6 of 388 proband chromosomes (frequency: 0.0155) from individuals or families with Alport syndrome and steroid-resistant nephrotic syndrome/focal segmental glomerulosclerosis (Fallerini_2017_PMID:27859054, Bullich_2015_PMID:25407002, Gillion_2018_PMID:29854973, Heidet_2001_PMID:11134255). The variant was also identified in dbSNP (ID: rs190598500), ClinVar (classified as conflicting interpretations of pathogenicity with uncertain significance reported by Counsyl and likely pathogenic reported by EGL Genetic Diagnostics; associated condition is Alport syndrome), and LOVD 3.0; it was not identified in the Cosmic database. The variant was identified in control databases in 102 of 280750 chromosomes at a frequency of 0.000363 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: Latino in 32 of 35360 chromosomes (freq: 0.000905), Other in 6 of 7144 chromosomes (freq: 0.00084), European (non-Finnish) in 63 of 128552 chromosomes (freq: 0.00049) and African in 1 of 24178 chromosomes (freq: 0.000041), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly1277 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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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