Submissions for variant NM_000091.5(COL4A3):c.3325C>T (p.Pro1109Ser)

gnomAD frequency: 0.00412  dbSNP: rs55816283

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000954602	SCV000717917	benign	not provided	2019-02-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14871398, 12028435, 17216251, 29981437)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000243309	SCV000967195	likely benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing	p.Pro1109Ser in exon 38 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 0.56% (376/66566) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs55816283).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000954602	SCV001101247	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001138911	SCV001299005	uncertain significance	Alport syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000954602	SCV002496641	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	COL4A3: BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294099	SCV002587500	benign	Kidney disorder	2019-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000243309	SCV002600348	benign	not specified	2022-10-08	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.3325C>T (p.Pro1109Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0042 in 280758 control chromosomes with 7 homozygotes (gnomAD), occuring predominantly at a frequency of 0.0057 within the Non-Finnish European subpopulation in the gnomAD database with 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3325C>T has been reported in the literature in individuals affected with Kidney Disorders (Longo_2002, Wang_2004, Papazachariou_2014, Kovacs_2016), often times reported as a polymorphism due to its heterozygosity index (Wang_2004), high mean allele frequency (Papazachariou_2014), or other variants being causitive of disease (Kovacs_2016). These reports suggest the variant is not likely to be associated with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003891831	SCV000302073	benign	COL4A3-related disorder	2019-07-31	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000243309	SCV001930444	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000954602	SCV001959391	likely benign	not provided		no assertion criteria provided	clinical testing