Submissions for variant NM_000092.5(COL4A4):c.2906C>G (p.Ser969Ter)

gnomAD frequency: 0.00011  dbSNP: rs35138315

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522361	SCV000617815	pathogenic	not provided	2021-08-03	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; This variant is associated with the following publications: (PMID: 31980526, 32723786, 12325029, 30647093, 25525159, 30406062, 29431110, 26346198, 24052634)
Fulgent Genetics, Fulgent Genetics	RCV000763076	SCV000893587	pathogenic	Autosomal recessive Alport syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000522361	SCV001228460	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser969*) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is present in population databases (rs35138315, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 12325029, 24052634). ClinVar contains an entry for this variant (Variation ID: 449549). For these reasons, this variant has been classified as Pathogenic.
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000763076	SCV001305529	pathogenic	Autosomal recessive Alport syndrome	2020-05-27	criteria provided, single submitter	research
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001171331	SCV001328278	pathogenic	Chronic kidney disease	2020-05-28	criteria provided, single submitter	research	PVS1, PS1
Baylor Genetics	RCV000763076	SCV001525716	pathogenic	Autosomal recessive Alport syndrome	2018-12-18	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000522361	SCV002017465	pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000763076	SCV002503761	pathogenic	Autosomal recessive Alport syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature termination codon at position 969 in exon 32 (of 48) of COL4A4 (p.Ser969*). It is expected to result in an absent or disrupted protein product in a gene where loss of function is a well-established mechanism of disease (PVS1). The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with a recessive condition (rs35138315, 18/280956 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2_Supporting). Furthermore, it has been reported as homozygous and compound heterozygous with a second pathogenic allele in multiple cases with Alport syndrome (PMID: 24052634 - PM3_Strong). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002279957	SCV002568146	pathogenic	COL4A4-related disorder	2022-05-26	criteria provided, single submitter	clinical testing	PVS1, PS1_Supporting, PM2, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000763076	SCV003844745	pathogenic	Autosomal recessive Alport syndrome	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: COL4A4 c.2906C>G (p.Ser969X) 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 associated with Alport Syndrome in HGMD. The variant allele was found at a frequency of 6.8e-05 in 249564 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (6.8e-05 vs 0.0016), allowing no conclusion about variant significance. c.2906C>G has been reported in the literature in multiple individuals affected with Alport Syndrome, Autosomal Recessive (Dagher_2002, Storey_2013, etc). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV002279957	SCV004105830	pathogenic	COL4A4-related disorder	2024-02-21	criteria provided, single submitter	clinical testing	The COL4A4 c.2906C>G variant is predicted to result in premature protein termination (p.Ser969*). This variant has been reported to be pathogenic for autosomal recessive Alport syndrome (see for example, Dagher et al. 2002. PubMed ID: 12325029; Storey et al. 2013. PubMed ID: 24052634; Gast et al. 2015. PubMed ID: 26346198). In addition, this variant in the heterozygous (carrier) state has been reported in an individual with recurrent and persistent hematuria (Barton et al. 2022. PubMed ID: 35649421). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in COL4A4 are expected to be pathogenic. This variant is interpreted as pathogenic for both autosomal dominant and autosomal recessive COL4A4-related conditions.
Counsyl	RCV000763076	SCV001132367	pathogenic	Autosomal recessive Alport syndrome	2016-11-18	no assertion criteria provided	clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001277168	SCV001449261	pathogenic	Alport syndrome	2018-04-03	no assertion criteria provided	clinical testing	This individual is heterozygous for a pathogenic variant c.2906C>G in the COL4A4 gene. This variant creates a premature stop codon p.(Ser969*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been widely reported in patients with autosomal recessive Alport syndrome (Storey et al 2013 J Am Soc Nephrol 24: 1945-1954), and some patients with thin basement membrane nephropathy (Buzza et al 2003 Kidney Int 63:447-453). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.006% (18/ 277, 194 alleles). This variant is considered to be pathogenic according to the ACMG guidelines.
Natera, Inc.	RCV001277168	SCV001464031	pathogenic	Alport syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542734	SCV001760075	likely pathogenic	Benign familial hematuria		no assertion criteria provided	clinical testing