ClinVar Miner

Submissions for variant NM_000091.4(COL4A3):c.2083G>A (p.Gly695Arg) (rs200287952)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001294 SCV001158474 pathogenic not specified 2019-06-21 criteria provided, single submitter clinical testing
Invitae RCV001240936 SCV001413921 uncertain significance not provided 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 695 of the COL4A3 protein (p.Gly695Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200287952, ExAC 0.03%). This variant has been observed in several individuals affected with autosomal dominant Alport syndrome (PMID: 14871398, 25229338, 29098738, Invitae). ClinVar contains an entry for this variant (Variation ID: 369964). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000408794 SCV001427184 pathogenic Alport syndrome 3, autosomal dominant 2019-03-14 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive (Alport syndrome) and dominant (Alport syndrome and benign familial hematuria) disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine (exon 28). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (31 heterozygotes, 0 homozygotes). (P) 0600 - Variant is located in an annotated motif (G-X-Y repeat in a triple helix motif; NCBI, PDB). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple substitutions of glycine in the G-X-Y motif within the collagen triple helix domain have been reported pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously described as pathogenic and segregated with disease in families with either thin basement membrane nephropathy (TBMN) or autosomal recessive Alport syndrome (ARAS) (ClinVar; PMID: 30476138; PMID: 14871398; PMID: 29854973; PMID: 24130771; PMID: 24052634; PMID: 25229338; PMID: 23325022; PMID: 29098738). (P) 1206 - Variant is paternally inherited. However, it is suggested that carriers may present with milder symptoms (PMID: 30450445), which can potentially be difficult to diagnose (PMID: 28704582). (N)
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000408794 SCV000484947 pathogenic Alport syndrome 3, autosomal dominant 2018-06-14 no assertion criteria provided clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000408794 SCV001439344 likely pathogenic Alport syndrome 3, autosomal dominant 2020-09-01 no assertion criteria provided clinical testing

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