rs104886303
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_033380.3(COL4A5):c.4964T>G(p.Leu1655Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_033380.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
X-linked Alport syndrome Pathogenic:4Other:1
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The COL4A5 c.4946T>G; p.Leu1649Arg variant (rs104886303), also reported as Leu1655Arg, has been described in multiple individuals and families affected with Alport syndrome and is associated with a mild phenotype presenting in adulthood (Barker 1996, Barker 2001, Kobayashi 2008, Martin 1998, Pont-Kingdon 2009). It is reported as pathogenic by multiple sources in ClinVar (Variation ID: 10466), and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 1649 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In agreement with this, in vitro analysis of the variant protein demonstrates defective trimerization, leading to secretion of a less stable monomeric alpha chain (Kobayashi 2008). Based on available information, this variant is considered pathogenic. REFERENCES Barker D et al. A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. Am J Hum Genet. 1996 Jun;58(6):1157-65. Barker D et al. Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. Am J Med Genet. 2001 Jan 15;98(2):148-60. Kobayashi T et al. Mutational analysis of type IV collagen alpha5 chain, with respect to heterotrimer formation. Biochem Biophys Res Commun. 2008 Feb 1;366(1):60-5. 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. Pont-Kingdon G et al. Molecular testing for adult type Alport syndrome. BMC Nephrol. 2009 Nov 17;10:38. -
not provided Pathogenic:4
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Also known as p.(L1649R) due to alternative nomenclature; Individuals previously reported with this variant were noted to have relatively mild Alport syndrome with onset in the 4th or 5th decade, with late hearing loss approximately 10 years after the onset of renal failure (Barker et al, 1996); This variant is associated with the following publications: (PMID: 17396119, 24470729, 19919694, 20301386, 18083113, 8651292, 27627812, 30647093, 23572034, 11223851, 9848783) -
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1649 of the COL4A5 protein (p.Leu1649Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 8651292, 23572034). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10466). 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%. Experimental studies have shown that this missense change affects COL4A5 function (PMID: 18083113). For these reasons, this variant has been classified as Pathogenic. -
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.5148T>G, p.L1649R. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. Introduction of this variant into the mouse homologue resulted in defective formation of the collagen heterotrimer (PMID: 18083113). Computational tools predict that this variant is damaging. -
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COL4A5-related disorder Pathogenic:1
The COL4A5 c.4946T>G variant is predicted to result in the amino acid substitution p.Leu1649Arg. This variant has been reported in multiple individuals with Alport syndrome (Barker et al. 1996. PubMed ID: 8651292; Pont-Kingdon et al. 2009. PubMed ID: 19919694; Yao et al. 2019. PubMed ID: 30647093). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -
Alport syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at