Submissions for variant NM_000091.5(COL4A3):c.4510T>C (p.Phe1504Leu)

gnomAD frequency: 0.00024  dbSNP: rs201671013

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597276	SCV000705460	uncertain significance	not provided	2017-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764366	SCV000895400	uncertain significance	Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825318	SCV000966613	uncertain significance	not specified	2018-10-09	criteria provided, single submitter	clinical testing	The p.Phe1504Leu variant in COL4A3 was identified in the heterozygous state in 1 Portuguese individual with Alport syndrome or thin basement membrane nephropath y (Sa 2015). It has also been identified in several populations by gnomAD, inclu ding 0.09% (9/10150) of Ashkenazi Jewish chromosomes and 0.02% (30/126604) of Eu ropean chromosomes (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, the clinical significance of this variant is uncertain. ACMG/AMP Crit eria applied: PP3, BS1_Supporting.
Mendelics	RCV000987048	SCV001136236	uncertain significance	Autosomal recessive Alport syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139014	SCV001299120	uncertain significance	Alport syndrome	2017-04-28	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.
GeneDx	RCV000597276	SCV001875227	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	Observed in a patient with Alport syndrome and thin basement membrane nephropathy and in a patient with blindness; however, additional patient-specific clinical information not provided (Nabais et al., 2015; Dieiro et al., 2020); 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: 34426522, 34013111, 25307543, 32483926)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825318	SCV002547822	uncertain significance	not specified	2022-05-26	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.4510T>C (p.Phe1504Leu) results in a non-conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of 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 0.00025 in 249428 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.00025 vs 0.0019), allowing no conclusion about variant significance. c.4510T>C has been reported in the literature as a non-informative genotype (second allele not specified) and a classification of VUS in at-least one individual within a cohort of Portuguese families with Alport Syndrome and Thin Basement Membrane Nephropathy analyzed for COL4A3 and COL4A4 variations (example, Nabais_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000597276	SCV003278845	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000597276	SCV001963149	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000597276	SCV001970199	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001139014	SCV002076432	uncertain significance	Alport syndrome	2020-01-19	no assertion criteria provided	clinical testing