Submissions for variant NM_000092.5(COL4A4):c.2144C>T (p.Ala715Val)

gnomAD frequency: 0.00021  dbSNP: rs76636743

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825911	SCV000967396	uncertain significance	not specified	2018-10-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala715Val var iant in COL4A4 has been identified in Greek-Cypriot individuals with glomerular microscopic hematuria; however, it was reported as a polymorphism based on its f requency in the Cypriot population (reported as 1%, though it is unclear how man y individuals were tested; Papazachariou 2014). This variant was also identified in 0.03% (9/29216) of South Asian chromosomes and 0.01% (17/124530) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational predict ion tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogeni city. In summary, though its frequency in the Cypriot population suggests it is more likely to be benign, the clinical significance of the p.Ala715Val variant i s uncertain. ACMG/AMP Criteria applied: BP4.
Athena Diagnostics Inc	RCV000991618	SCV001143230	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001140966	SCV001301275	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	RCV000991618	SCV001767012	uncertain significance	not provided	2020-10-09	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients with nephrotic syndrome in published literature (McCarthy et al., 2013); however, patient-level clinical information was not provided; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23349334, 25514610)
Invitae	RCV000991618	SCV002363015	likely benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000991618	SCV003916252	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	COL4A4: BP5
Natera, Inc.	RCV001140966	SCV002078906	uncertain significance	Alport syndrome	2020-01-21	no assertion criteria provided	clinical testing