Submissions for variant NM_000092.5(COL4A4):c.4678C>T (p.Arg1560Cys)

gnomAD frequency: 0.00008  dbSNP: rs200973262

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000342956	SCV000428065	uncertain significance	Alport syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV001265753	SCV001443922	uncertain significance	Inborn genetic diseases	2020-06-04	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change: The c.4678C>T (p.R1560C) alteration is located in exon 47 (coding exon 46) of the COL4A4 gene. This alteration results from a C to T substitution at nucleotide position 4678, causing the arginine (R) at amino acid position 1560 to be replaced by a cysteine (C). The alteration has been observed in population databases: Based on data from the Genome Aggregation Database (gnomAD), the c.4678C>T alteration was observed in 0.0068% (19/280,236) of total alleles studied, with a frequency of 0.011% (14/128,228) in the non-Finnish European subpopulation. The altered amino acid is not conserved throughout evolution: The p.R1560 amino acid is not conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling: The p.R1560C alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV001330986	SCV001522866	uncertain significance	Autosomal recessive Alport syndrome	2020-08-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001770271	SCV002002286	uncertain significance	not provided	2020-07-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001770271	SCV002339142	likely benign	not provided	2023-12-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001330986	SCV004805433	uncertain significance	Autosomal recessive Alport syndrome	2024-03-25	criteria provided, single submitter	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV001029898	SCV001192693	uncertain significance	Autosomal dominant Alport syndrome	2019-03-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000342956	SCV002078857	uncertain significance	Alport syndrome	2019-10-28	no assertion criteria provided	clinical testing