Submissions for variant NM_000092.5(COL4A4):c.4715C>T (p.Pro1572Leu)

gnomAD frequency: 0.00019  dbSNP: rs121912863

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825912	SCV000967397	uncertain significance	not specified	2019-03-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001140736	SCV001301022	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001245590	SCV001418888	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001245590	SCV001789747	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	Observed with a second variant in a patient with mesangial proliferative nephropathy in published literature (Lin et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31019026, 31589614, 32154576, 25381091, 9792860, 22887978, 35114279, 36370330, 33772369, 36349777)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002293986	SCV002587139	uncertain significance	Kidney disorder	2019-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825912	SCV003844672	uncertain significance	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: COL4A4 c.4715C>T (p.Pro1572Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 248514 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (0.00016 vs 0.0016), allowing no conclusion about variant significance. c.4715C>T has been reported in the literature in individuals affected with Alport Syndrome, Autosomal Recessive. These reports do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV001245590	SCV004699310	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing
OMIM	RCV000018952	SCV000039239	pathogenic	Autosomal recessive Alport syndrome	1998-11-01	flagged submission	literature only
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001140736	SCV002047444	likely pathogenic	Alport syndrome		flagged submission	research