Submissions for variant NM_033380.3(COL4A5):c.665T>G (p.Phe222Cys)

dbSNP: rs281874761

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000405636	SCV000329766	pathogenic	not provided	2016-08-23	criteria provided, single submitter	clinical testing	The F222C variant in the COL4A5 gene has been previously reported in affected males from two families with Alport syndrome (Becknell et al., 2011; Wuttke et al., 2015). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. F222C 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, missense variants in nearby residues (G216R/E/V, G219S, G227S/D) 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. Therefore, we consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032053	SCV001431957	pathogenic	X-linked Alport syndrome	2022-02-04	criteria provided, single submitter	clinical testing	Variant summary: COL4A5 c.665T>G (p.Phe222Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181287 control chromosomes (gnomAD). c.665T>G has been reported in the literature in multiple male individuals from 3 families, who were affected with Alport Syndrome 1, X-Linked Recessive (Becknell_2011, Wuttke_2015, Barua_2018); and the variant co-segregated with the disease in all of these families. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000405636	SCV002236505	pathogenic	not provided	2021-08-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is not expected to disrupt COL4A5 protein function. This variant has been observed in individual(s) with glomerular disease (PMID: 20881942, 26613025, 29198386). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38751). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 222 of the COL4A5 protein (p.Phe222Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine.