rs773515249
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000091.5(COL4A3):c.1855G>A(p.Gly619Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G619E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000091.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.1855G>A | p.Gly619Arg | missense_variant | 26/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.423-4276C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.1855G>A | p.Gly619Arg | missense_variant | 26/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.423-4276C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000810 AC: 2AN: 246972Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134254
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461814Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727214
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive Alport syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Precision Medicine Center, Zhengzhou University | - | PM1:Located in a mutational hot spot PM2:not found in gnomAD PP2:Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 05, 2023 | Variant summary: COL4A3 c.1855G>A (p.Gly619Arg) results in a non-conservative amino acid change in the encoded protein sequence altering a Glycine residue within the triple-helical region. Alterations of Glycine residues within the collagen triple-helix are common mechanisms of disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246972 control chromosomes. c.1855G>A has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in individuals affected with features of autosomal recessive Alport Syndrome and as a heterozygous presumably dominant genotype in individuals affected with features of autosomal dominant Alport Syndrome (example, Horinouchi_2020, Garcia-Aznar_2022, Moriniere_2014, Oka_2014, Xie_2014, Kamiyoshi_2016, Jayasinghe_2021, Wang_2021). In at-least one instance, both carrier parents of an affected homozygote were reportedly asymptomatic (Xie_2014). These data indicate that the variant is very likely to be associated with disease although an exact inheritance pattern cannot be specified. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Zhang_2019). The following publications have been ascertained in the context of this evaluation (PMID: 36013122, 35369551, 32939031, 27281700, 24854265, 24633401, 34215756, 25596306, 31306228). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic (n=1) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 619 of the COL4A3 protein (p.Gly619Arg). This variant is present in population databases (rs773515249, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive Alport syndrome (PMID: 24633401, 25596306, 34215756). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 522482). 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 COL4A3 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on COL4A3 function (PMID: 31306228). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Autosomal dominant Alport syndrome Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Sep 18, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 30, 2018 | A heterozygous missense variant, NM_000091.4(COL4A3):c.1855G>A, has been identified in exon 26 of 52 of the COL4A3 gene. The variant is predicted to result in a major amino acid change from glycine to arginine at position 619 of the protein, NP_000082.2(COL4A3):p.(Gly619Arg). The glycine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the collagen triple-helical domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0008% (2 heterozygotes). The variant has previously been reported in families with either autosomal recessive or dominant Alport syndrome (ClinVar, Moriniere, V., et al. (2014), Oka, M., et al. (2014), Xie, J., et al. (2014)). In addition, it has been described as a VUS in a patient with steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis (Sen, E., et al. (2017)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. - |
Benign familial hematuria;C5882663:Autosomal dominant Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics, University of Parma | Mar 11, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at