ClinVar Miner

Submissions for variant NM_033380.3(COL4A5):c.4709G>C (p.Cys1570Ser) (rs104886287)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000021640 SCV001158664 pathogenic Alport syndrome 1, X-linked recessive 2019-04-11 criteria provided, single submitter clinical testing The COL4A5 c.4691G>C; p.Cys1564Ser variant (rs104886287) is reported in the medical literature segregating with Alport syndrome in a large kindred (Pont-Kingdon 2009, Zhou 1991). It is reported as pathogenic in ClinVar (Variation ID: 24761) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 1564 is highly conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Additionally, this is one of twelve cysteine residues located in the carboxy-terminal domain important for formation of triple helices or networks involving collagen alpha5(IV) chains (Kashtan 2001). Based on available information, this variant is considered pathogenic. References: Kashtan CE. Alport Syndrome and Thin Basement Membrane Nephropathy. 2001 Aug 28 (Updated 2015 Nov 25). In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1207/ Pont-Kingdon G et al. Molecular testing for adult type Alport syndrome. BMC Nephrol. 2009 Nov 17;10:38. doi: 10.1186/1471-2369-10-38. Zhou J et al. Single base mutation in alpha 5(IV) collagen chain gene converting a conserved cysteine to serine in Alport syndrome. Genomics. 1991 Jan;9(1):10-8.
Invitae RCV001047411 SCV001211368 pathogenic not provided 2020-01-10 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 1564 of the COL4A5 protein (p.Cys1564Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with adult-onset X-linked Alport syndrome (PMID: 1672282, 19919694, 8651292). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24761). This variant has been reported to affect COL4A5 protein function (PMID: 18083113). For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV000021640 SCV000042306 moderate Alport syndrome 1, X-linked recessive 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
GeneReviews RCV000021640 SCV000057824 pathologic Alport syndrome 1, X-linked recessive 2013-02-28 no assertion criteria provided curation Converted during submission to Pathogenic.

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