Submissions for variant NM_033380.3(COL4A5):c.4964T>G (p.Leu1655Arg) (rs104886303)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Athena Diagnostics Inc	RCV000440813	SCV000612998	pathogenic	not provided	2021-04-14	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.5148T>G, p.L1649R. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. Introduction of this variant into the mouse homologue resulted in defective formation of the collagen heterotrimer (PMID: 18083113). Computational tools predict that this variant is damaging.
Fulgent Genetics,Fulgent Genetics	RCV000011212	SCV000893815	pathogenic	Alport syndrome 1, X-linked recessive	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000440813	SCV000965555	pathogenic	not provided	2020-08-19	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 in individual(s) with Alport syndrome (PMID: 8651292, 23572034). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10466). This variant has been reported to affect COL4A5 protein function (PMID: 18083113). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000011212	SCV001156656	pathogenic	Alport syndrome 1, X-linked recessive	2019-12-16	criteria provided, single submitter	clinical testing	The COL4A5 c.4946T>G; p.Leu1649Arg variant (rs104886303), also reported as Leu1655Arg, has been described in multiple individuals and families affected with Alport syndrome and is associated with a mild phenotype presenting in adulthood (Barker 1996, Barker 2001, Kobayashi 2008, Martin 1998, Pont-Kingdon 2009). It is reported as pathogenic by multiple sources in ClinVar (Variation ID: 10466), and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 1649 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In agreement with this, in vitro analysis of the variant protein demonstrates defective trimerization, leading to secretion of a less stable monomeric alpha chain (Kobayashi 2008). Based on available information, this variant is considered pathogenic. REFERENCES Barker D et al. A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. Am J Hum Genet. 1996 Jun;58(6):1157-65. Barker D et al. Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. Am J Med Genet. 2001 Jan 15;98(2):148-60. Kobayashi T et al. Mutational analysis of type IV collagen alpha5 chain, with respect to heterotrimer formation. Biochem Biophys Res Commun. 2008 Feb 1;366(1):60-5. Martin P et al. High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing. J Am Soc Nephrol. 1998 Dec;9(12):2291-301. Pont-Kingdon G et al. Molecular testing for adult type Alport syndrome. BMC Nephrol. 2009 Nov 17;10:38.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill	RCV001195698	SCV001366102	pathogenic	Alport syndrome	2018-10-31	criteria provided, single submitter	clinical testing
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.
GeneReviews	RCV000011212	SCV000057825	pathologic	Alport syndrome 1, X-linked recessive	2013-02-28	no assertion criteria provided	curation	Converted during submission to Pathogenic.