ClinVar Miner

Submissions for variant NM_000495.5(COL4A5):c.4946T>G (p.Leu1649Arg) (rs104886303)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000440813 SCV000612998 pathogenic not provided 2017-06-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000011212 SCV000893815 pathogenic Alport syndrome 1, X-linked recessive 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000440813 SCV000515887 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing The L1655R missense variant in the COL4A5 gene has been reported previously in association with Alportsyndrome (Barker et al., 1996; Barker et al., 2001; Martin et al., 1998). Individuals previously reported with this variant were noted to have relatively mild Alport syndrome with onset in the 4th or 5th decade, with late hearing loss approximately 10 years after the onset of renal failure (Barker et al, 1996). The L1655R substitution was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating itis not a common benign variant in these populations. Furthermore, other missense variants in nearbyresidues (S1659G, S1659N) have been reported in association with Alport syndrome in the Human GeneMutation Database (Stenson et al., 2014). L1655R is a non-conservative amino acid substitution resulting inthe replacement of a neutral non-polar Leucine residue with a positively charged Arginine residue in the NC1domain. Therefore, we interpret L1655R to be pathogenic.
GeneReviews RCV000011212 SCV000057825 pathologic Alport syndrome 1, X-linked recessive 2013-02-28 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000440813 SCV000965555 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 1649 of the COL4A5 protein (p.Leu1649Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs104886303, ExAC 0.002%). This variant has been observed to segregate with Alport syndrome in several families (PMID: 8651292, 23572034). ClinVar contains an entry for this variant (Variation ID: 10466). Experimental studies have shown that this missense change impairs protein function (PMID: 18083113). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000011212 SCV000031439 pathogenic Alport syndrome 1, X-linked recessive 1996-06-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000011212 SCV000042326 moderate Alport syndrome 1, X-linked recessive 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.

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