ClinVar Miner

Submissions for variant NM_033380.3(COL4A5):c.1871G>A (p.Gly624Asp) (rs104886142)

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Total submissions: 16
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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 2021-05-07 criteria provided, single submitter clinical testing 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, and benign familial hematuria (Martin et al., 1998; Tan et al., 2010; Demosthenous et al., 2012; Slajpah et al., 2007; Pierides et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene; This variant is associated with the following publications: (PMID: 21332469, 30661074, 19965530, 29854973, 28844315, 33309955, 17396119, 11223851, 9848783, 26809805, 24470729, 30691124, 26934356, 20378821, 19728970, 31850286, 33352548, 31754267, 32359821, 33226606, 33233744)
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414817 SCV000492878 pathogenic Mild proteinuria; Glomerulopathy; Hypertensive disorder 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 2020-10-21 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000324895 SCV001245928 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000021334 SCV001369450 pathogenic Alport syndrome 1, X-linked recessive 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000021334 SCV001428477 pathogenic Alport syndrome 1, X-linked recessive 2019-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000021334 SCV001467733 pathogenic Alport syndrome 1, X-linked recessive 2020-12-21 criteria provided, single submitter clinical testing Variant summary: COL4A5 c.1871G>A (p.Gly624Asp) results in a non-conservative amino acid change in the encoded protein sequence. This variant is positioned right before the 12th natural tripeptide Gly-X-Y interruption which is of G1G type, thereby converting it to a G4G interruption in the collagenous domain (Demosthenous_2011). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 182998 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in COL4A5 causing Alport Syndrome 1, X-Linked Recessive (8.7e-05 vs 0.0046), allowing no conclusion about variant significance. c.1871G>A has been reported in the literature in multiple individuals affected with Alport Syndrome, benign familial hematuria, end-stage renal disease and thin basement membrane nephropathy (Martin_1998, Slajpah_2007, Demosthenous_2011, Weber_2016). 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. 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and pathogenic (10x). Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000021334 SCV001472103 pathogenic Alport syndrome 1, X-linked recessive 2019-08-30 criteria provided, single submitter clinical testing The COL4A5 c.1871G>A; p.Gly624Asp variant (rs104886142) is reported in the literature in multiple individuals and families affected with Alport syndrome, but is associated with a mild form of disease, including individuals with benign familial hematuria (Demosthenous 2012, Kovacs 2016, Martin 1998, Pierides 2013, Slajpah 2007, Tan 2010, Weber 2016). This variant is reported in ClinVar (Variation ID: 24455), and is found in the non-Finnish European population with an allele frequency of 0.020% (16/81695 alleles, including 4 hemizygotes) in the Genome Aggregation Database. The glycine at codon 624 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. However, this variant disrupts the repeating Gly-X-Y sequence motif of the collagen triple helix and is predicted to impair collagen function (Persikov 2004, Weerakkody 2016). Based on available information, this variant is considered to be pathogenic. References: Demosthenous P et al. X-linked Alport syndrome in Hellenic families: phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5. Clin Genet. 2012 Mar;81(3):240-8. Kovacs G et al. Efficient Targeted Next Generation Sequencing-Based Workflow for Differential Diagnosis of Alport-Related Disorders. PLoS One. 2016 Mar 2;11(3):e0149241. Martin P et al. High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing. J Am Soc Nephrol. 1998 Dec;9(12):2291-301. Pierides A eta l. X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure. Hippokratia. 2013 Jul;17(3):207-13. Persikov AV et al. Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum Mutat. 2004 Oct;24(4):330-7. Slajpah M et al. Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney Int. 2007 Jun;71(12):1287-95. Tan R et al. Alport retinopathy results from "severe" COL4A5 mutations and predicts early renal failure. Clin J Am Soc Nephrol. 2010 Jan;5(1):34-8. Weber S et al. Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. Pediatr Nephrol. 2016 Jun;31(6):941-55. Weerakkody RA et al. Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome. Genet Med. 2016 Nov;18(11):1119-1127.
Fulgent Genetics,Fulgent Genetics RCV000021334 SCV001752712 pathogenic Alport syndrome 1, X-linked recessive 2021-06-30 criteria provided, single submitter clinical testing
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.
Counsyl RCV000021334 SCV001132372 uncertain significance Alport syndrome 1, X-linked recessive 2018-12-21 no assertion criteria provided clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000021334 SCV001150062 pathogenic Alport syndrome 1, X-linked recessive 2019-05-10 no assertion criteria provided clinical testing
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328295 SCV001449280 pathogenic Alport syndrome 2015-01-31 no assertion criteria provided clinical testing This patient is hemizygous for a known pathogenic variant, c.1871G>A p.(Gly624Asp), in exon 25 of the COL4A5 gene. This variant (dbSNP: rs104886142) results in substitution of one of the invariant glycine residues in the triple helical domain of type I collagen, and is considered to be pathogenic. This variant has been previously described in patients with Alport syndrome and benign familial hematuria in the Alport database (see http://www.arup.utah.edu/database/alport/alport_welcome.php).

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