ClinVar Miner

Submissions for variant NM_000495.5(COL4A5):c.1871G>A (p.Gly624Asp) (rs104886142)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Diagnostic Laboratory,University of Szeged RCV000021334 SCV000262768 pathogenic Alport syndrome 1, X-linked recessive 2016-02-02 criteria provided, single submitter clinical testing
GeneDx RCV000324895 SCV000329310 pathogenic not provided 2018-12-13 criteria provided, single submitter clinical testing The G624D pathogenic variant in the COL4A5 gene may be associated with milder disease as it has been reported previously in association with Alport syndrome, as well as late-onset end stage renal disease, thin basement membrane nephropathy (TBMN), and benign familial hematuria (Martin et al., 1998; Tan et al., 2010; Demosthenous et al., 2012; Slajpah et al., 2007; Pierides et al., 2013). The G624D variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This non-conservative amino acid substitution occurs at a position that is conserved across species, affecting the Glycine residue of a triple-helical region containing Gly-X-Y repeats. Over one-third of the pathogenic variants reported in association with Alport syndrome are reported to be missense variants in which a Glycine residue is replaced by another amino acid in this region of the protein that contains numerous Gly-X-Y repeats (Stenson et al., 2014). Accordingly, missense variants in nearby Glycine residues (G621C, G621V, G626A, G629D) 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 G624D as a pathogenic variant.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414817 SCV000492878 pathogenic Mild proteinuria; Glomerulopathy; Hypertension 2015-04-13 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000324895 SCV000809122 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Athena Diagnostics Inc RCV000324895 SCV000841171 pathogenic not provided 2017-09-08 criteria provided, single submitter clinical testing
Invitae RCV000324895 SCV000965147 pathogenic not provided 2019-01-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 624 of the COL4A5 protein (p.Gly624Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs104886142, ExAC 0.01%). This variant has been observed in multiple individuals and families with COL4A5-related conditions (PMID: 24470729, 26934356, 21332469, 26809805, 17396119, 29854973). ClinVar contains an entry for this variant (Variation ID: 24455). For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV000021334 SCV000042000 moderate Alport syndrome 1, X-linked recessive 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.

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