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	2020-01-02	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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