Submissions for variant NM_000091.5(COL4A3):c.3644G>A (p.Arg1215Gln)

gnomAD frequency: 0.00011  dbSNP: rs200443942

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV001007587	SCV001167233	uncertain significance	Autosomal dominant Alport syndrome	2019-10-18	criteria provided, single submitter	clinical testing	COL4A3 c.3644G>A has been reported in an individual with a clinical diagnosis of Alport syndrome, however, it has not been reported in ClinVar, to our knowledge. This variant (rs200443942) is present in a large population dataset5 (gnomAD: 35/253468 total alleles; 0.014%; no homozygotes). This missense substitution is located within the collagenous domain of COL4A3. Three bioinformatic tools queried predict that this substitution would be tolerated, and the arginine residue at this position is poorly evolutionarily conserved across the species assessed. Due to insufficient evidence, we consider the clinical significance of c.3644G>A to be uncertain at this time.
Illumina Laboratory Services, Illumina	RCV001141512	SCV001301863	uncertain significance	Alport syndrome	2018-01-12	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.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001248769	SCV001422278	uncertain significance	Autosomal recessive Alport syndrome	2019-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001702764	SCV002072706	uncertain significance	not provided	2022-01-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; 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
Invitae	RCV001702764	SCV002479865	likely benign	not provided	2023-12-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702764	SCV001932056	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702764	SCV001974843	likely benign	not provided		no assertion criteria provided	clinical testing