Submissions for variant NM_000092.5(COL4A4):c.1396G>A (p.Gly466Arg)

gnomAD frequency: 0.00002  dbSNP: rs201859109

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518015	SCV000612959	pathogenic	not provided	2016-08-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481668	SCV002788888	pathogenic	Autosomal recessive Alport syndrome; Benign familial hematuria	2021-07-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000518015	SCV003524981	likely pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 466 of the COL4A4 protein (p.Gly466Arg). This variant is present in population databases (rs201859109, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant COL4A4-related conditions (PMID: 26809805, 29801666; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447180). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A4 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787824	SCV005399231	pathogenic	Alport syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are mechanisms of disease in this gene and are associated with both Alport Syndrome and Thin Basement Membrane Nephropathy. Loss of function is an established mechanism of disease while dominant negative is a suspected mechanism of disease as COL4A4 is a structural protein (PMIDs: 12028435; 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). Thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inhertitance (OMIM, PMID: 16467446; 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established triple-helical region (NCBI conserved domain). (SP) 0803 - This variant has limited previous evidence of pathogenicity in 2 unrelated individuals. This variant has been reported in heterozygous state in one individual with Thin Basement Membrane Nephropathy, and one individual with Alport Syndrome, respectively (PMIDs: 26809805, 29801666). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796219	SCV005418918	uncertain significance	Autosomal recessive Alport syndrome; Hematuria, benign familial, 1		criteria provided, single submitter	clinical testing	PM2+PP3
Counsyl	RCV000984248	SCV001132368	uncertain significance	Autosomal recessive Alport syndrome	2019-01-24	no assertion criteria provided	clinical testing