Submissions for variant NM_033380.3(COL4A5):c.796C>T (p.Arg266Ter)

dbSNP: rs104886071

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518117	SCV000613002	pathogenic	not provided	2017-07-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000021203	SCV001524844	pathogenic	X-linked Alport syndrome	2019-12-30	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000518117	SCV001591114	pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg266*) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 15780079, 17396119, 29854973). ClinVar contains an entry for this variant (Variation ID: 24325). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000518117	SCV001778269	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15780079, 25525159, 15954103, 17396119)
Fulgent Genetics, Fulgent Genetics	RCV000021203	SCV002806224	pathogenic	X-linked Alport syndrome	2024-04-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000021203	SCV005876512	pathogenic	X-linked Alport syndrome	2024-02-21	criteria provided, single submitter	clinical testing	The COL4A5 c.796C>T; p.Arg266Ter variant (rs104886071) is reported in the literature in several heterozygous and hemizygous individuals with symptoms of Alport syndrome (Gillion 2018, Kim 2023, Mastrangelo 2020, Nagel 2005, Rao 2019, Slajpah 2007, Wang 2005). This variant is reported as pathogenic in ClinVar (Variation ID: 24325). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Gillion V et al. Genotype and Outcome After Kidney Transplantation in Alport Syndrome. Kidney Int Rep. 2018 Feb 2;3(3):652-660. PMID: 29854973. Kim JH et al. Genotype-phenotype correlation of X-linked Alport syndrome observed in both genders: a multicenter study in South Korea. Sci Rep. 2023 Apr 26;13(1):6827. PMID: 37100867. Mastrangelo A et al. X-Linked Alport Syndrome in Women: Genotype and Clinical Course in 24 Cases. Front Med (Lausanne). 2020 Nov 23;7:580376. PMID: 33330536. Nagel M et al. Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome. Hum Mutat. 2005 Jul;26(1):60. PMID: 15954103. Rao J et al. Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system. Clin Genet. 2019 Nov;96(5):402-410. PMID: 31328266. Slajpah M et al. Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney Int. 2007 Jun;71(12):1287-95. PMID: 17396119. Wang F et al. Detection of mutations in the COL4A5 gene by analyzing cDNA of skin fibroblasts. Kidney Int. 2005 Apr;67(4):1268-74. PMID: 15780079.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328292	SCV001449277	pathogenic	Alport syndrome	2018-09-10	no assertion criteria provided	clinical testing	This patient is heterozygous for a known pathogenic variant, c.796C>T, in the COL4A5 gene. This variant (dbSNP: rs104886071) creates a premature stop codon (p.Arg266*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been previously reported in the COL4A5 Alport database (http://www.arup.utah.edu/database/ALPORT/ALPORT_welcome.php) and is considered to be pathogenic.