Submissions for variant NM_033380.3(COL4A5):c.3088G>A (p.Gly1030Ser)

dbSNP: rs104886210

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387178	SCV001587741	pathogenic	not provided	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1030 of the COL4A5 protein (p.Gly1030Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 9848783, 24130771). ClinVar contains an entry for this variant (Variation ID: 24591). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL4A5 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001563661	SCV001786649	likely pathogenic	Alport syndrome	2021-02-25	criteria provided, single submitter	clinical testing	The COL4A5 c.3088G>A (p.Gly1030Ser) variant is a missense variant that has been reported in a hemizygous state in three male individuals and in a heterozygous state in one female individual with Alport syndrome (Martin et al. 1998; Wang et al. 2004; Liu et al. 2017; Kamura et al. 2020). All the affected individuals presented with hematuria, with two individuals also presenting with sensorineural hearing loss. The p.Gly1030Ser variant segregated in one family in which it was present in the affected father and son (Kamura et al. 2020). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so is presumed to be rare. Glycine substitutions in missense variants in the collagenous domain are the most common variant type found in X-linked Alport syndrome (Kamura et al. 2020). Circular dichroism spectroscopy studies showed that the p.Gly1030Ser variant affected secondary structure of the protein and results in less beta-sheet and more random coil structure compared to wild type (Wang et al. 2004). In addition, expression of the p.Gly1030Ser variant in HEK293T cells showed a significant reduction of over 50% in extracellular secretion of COL4A5 compared to wild type (Kamura et al. 2020). Based on the collective evidence, the p.Gly1030Ser variant is classified as likely pathogenic for Alport syndrome.
MGZ Medical Genetics Center	RCV002288515	SCV002580861	likely pathogenic	X-linked Alport syndrome	2022-06-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002288515	SCV002781687	pathogenic	X-linked Alport syndrome	2022-05-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001387178	SCV003803194	pathogenic	not provided	2023-02-08	criteria provided, single submitter	clinical testing	Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD; Jais et al., 2000); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15044104, 19919694, 29526710, 32405592, 9848783, 29127259, 15780079, 15347445, 33040356)
CeGaT Center for Human Genetics Tuebingen	RCV001387178	SCV004010957	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	COL4A5: PM1:Strong, PM2, PS4:Moderate, PP3, PP4
Yale Center for Mendelian Genomics, Yale University	RCV001849277	SCV002107068	likely pathogenic	Nephrotic syndrome	2017-11-10	no assertion criteria provided	literature only