Submissions for variant NM_000091.5(COL4A3):c.2768_2778del (p.Val923fs)

dbSNP: rs766306957

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666969	SCV000791349	pathogenic	Autosomal recessive Alport syndrome	2017-05-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000729022	SCV000856655	pathogenic	not provided	2017-09-20	criteria provided, single submitter	clinical testing
Invitae	RCV000729022	SCV001207327	pathogenic	not provided	2023-06-11	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 551819). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Alport syndrome (PMID: 24052634, 24854265). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs766306957, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Val923Glufs*13) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000666969	SCV001361059	pathogenic	Autosomal recessive Alport syndrome	2019-02-04	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.2768_2778del11 (p.Val923GlufsX13) 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. The variant allele was found at a frequency of 2.4e-05 in 246024 control chromosomes (gnomAD). c.2768_2778del11 has been reported in the literature in homozygous and compound heterozygous individuals affected with Alport Syndrome, autosomal recessive (Storey 2013, Moriniere 2014). These data indicate that the variant is likely to be associated with disease. 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, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000729022	SCV001758474	pathogenic	not provided	2019-12-27	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; This variant is associated with the following publications: (PMID: 30665703, 24052634, 24854265)
Natera, Inc.	RCV001273240	SCV001456035	pathogenic	Alport syndrome	2020-09-16	no assertion criteria provided	clinical testing