Submissions for variant NM_000091.5(COL4A3):c.686G>T (p.Arg229Leu)

dbSNP: rs188942711

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658171	SCV000779942	uncertain significance	not provided	2018-05-09	criteria provided, single submitter	clinical testing	The c.686 G>T variant in the COL4A3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.686 G>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico splice models predict that c.686 G>T may damage the natural splice donor site in intron 12, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of the c.686 G>T change in this individual is unknown. If c.686 G>T does not alter splicing, it will result in the R229L missense change. The R229L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (G223E, G230D) have been reported in the Human Gene Mutation Database in association with Alport syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret c.686 G>T as a variant of uncertain significance.
Illumina Laboratory Services, Illumina	RCV001141281	SCV001301616	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000658171	SCV002183386	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 229 of the COL4A3 protein (p.Arg229Leu). This variant is present in population databases (rs188942711, gnomAD 0.0009%). This missense change has been observed in individual(s) with Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 546314). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002493071	SCV002788196	uncertain significance	Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria	2022-05-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001141281	SCV001458835	uncertain significance	Alport syndrome	2020-01-24	no assertion criteria provided	clinical testing