Submissions for variant NM_000091.5(COL4A3):c.2417dup (p.Gly807fs)

dbSNP: rs1440033157

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667462	SCV000791913	likely pathogenic	Autosomal recessive Alport syndrome	2017-05-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000667462	SCV001150054	pathogenic	Autosomal recessive Alport syndrome	2019-06-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000667462	SCV001983759	likely pathogenic	Autosomal recessive Alport syndrome	2021-09-29	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.2417dupC (p.Gly807ArgfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.8e-06 in 172936 control chromosomes. c.2417dupC has been reported in the literature in at least one individual affected with Alport Syndrome, Autosomal Recessive (Heidet_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003148822	SCV003837027	pathogenic	not provided	2024-09-12	criteria provided, single submitter	clinical testing	Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36117978, 37217505, 11134255, 38346493)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003148822	SCV004294022	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly807Argfs*28) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Alport syndrome (PMID: 11134255). ClinVar contains an entry for this variant (Variation ID: 552236). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005019120	SCV005651302	pathogenic	Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive	2024-03-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742562	SCV005361927	pathogenic	COL4A3-related disorder	2024-08-02	no assertion criteria provided	clinical testing	The COL4A3 c.2417dupC variant is predicted to result in a frameshift and premature protein termination (p.Gly807Argfs*28). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Alport syndrome (Heidet et al. 2001. PubMed ID: 11134255; Table S1, Ćomić et al. 2022. PubMed ID: 36117978). This variant is reported in 0.0014% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in COL4A3 are expected to be pathogenic. This variant is interpreted as pathogenic.