ClinVar Miner

Submissions for variant NM_001846.4(COL4A2):c.4147G>A (p.Gly1383Arg)

gnomAD frequency: 0.00001  dbSNP: rs797044947
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000190797 SCV000244238 likely pathogenic Inborn genetic diseases 2014-10-20 criteria provided, single submitter clinical testing The c.4147G>A (p.G1383R) alteration is located in exon 44 (coding exon 43) of the COL4A2 gene. This alteration results from a G to A substitution at nucleotide position 4147, causing the glycine (G) at amino acid position 1383 to be replaced by an arginine (R). The alteration is not observed in healthy cohorts: Based on data from the NHLBI Exome Sequencing Project (ESP), the COL4A2 c.4147G>A alteration was not observed among 5,910 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES: Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered amino acid is conserved throughout evolution: The p.G1383 amino acid position is completely conserved in available vertebrate species. The amino acid is located in a functionally important protein domain: The p.G1383R amino acid is located within one of the G-X-Y repeats of the triple helical domain, which is essential for the normal folding of the triple helix. Most COL4A2 mutations in humans are substitutions of these conserved G residues and have a dominant negative effect upon protein function (reviewed in Yoneda, 2012 and Varbeek, 2012). The alteration is predicted deleterious by in silico models: The p.G1383R alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as likely pathogenic.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000761267 SCV000891225 likely pathogenic Porencephaly 2 2018-04-30 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000761267 SCV001934276 likely pathogenic Porencephaly 2 2020-10-28 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000761267 SCV002579771 uncertain significance Porencephaly 2 2021-12-02 criteria provided, single submitter clinical testing
GeneDx RCV001579761 SCV002765545 pathogenic not provided 2022-12-15 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24001601, 26708157, 25719457, 24390199, 22333902, 22209247, 22209246, 30413629)
Invitae RCV001579761 SCV003786632 pathogenic not provided 2022-08-11 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1383 of the COL4A2 protein (p.Gly1383Arg). This variant is not present in population databases (gnomAD no frequency). 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 expected to disrupt COL4A2 protein function. ClinVar contains an entry for this variant (Variation ID: 208773). This missense change has been observed in individual(s) with clinical features of COL4A2-related conditions (PMID: 30413629). In at least one individual the variant was observed to be de novo.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV001579761 SCV001808431 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001579761 SCV001956958 likely pathogenic not provided no assertion criteria provided clinical testing

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