rs104886142
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong
The NM_033380.3(COL4A5):c.1871G>A(p.Gly624Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000463 in 1,209,813 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000062 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.000045 ( 0 hom. 21 hem. )
Consequence
COL4A5
NM_033380.3 missense
NM_033380.3 missense
Scores
10
5
2
Clinical Significance
Conservation
PhyloP100: 9.31
Genes affected
COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
In a compositionally_biased_region Pro residues (size 22) in uniprot entity CO4A5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_033380.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.9
PP5
Variant X-108598793-G-A is Pathogenic according to our data. Variant chrX-108598793-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108598793-G-A is described in Lovd as [Pathogenic]. Variant chrX-108598793-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-108598793-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COL4A5 | ENST00000328300.11 | c.1871G>A | p.Gly624Asp | missense_variant | 25/53 | 1 | NM_033380.3 | ENSP00000331902.7 | ||
| COL4A5 | ENST00000483338.1 | c.695G>A | p.Gly232Asp | missense_variant | 9/20 | 1 | ENSP00000495685.1 | |||
| COL4A5 | ENST00000361603.7 | c.1871G>A | p.Gly624Asp | missense_variant | 25/51 | 2 | ENSP00000354505.2 |
Frequencies
GnomAD3 genomes 0.0000623 AC: 7AN: 112356Hom.: 0 Cov.: 23 AF XY: 0.0000579 AC XY: 2AN XY: 34520
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:30Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
X-linked Alport syndrome Pathogenic:20Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 30, 2019 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 22, 2022 | The COL4A5 c.1871G>A variant is classified as a PATHOGENIC variant (PS3, PS4, PM1, PP3, PP4) This variant is a single nucleotide change in exon 25/53 of the COL4A5 gene, which is predicted to change the amino acid glycine at position 624 in the protein to aspartic acid. The variant is located in protein domain: collagen triple helix repeat, of the COL4A5 gene. Missense variants in nearby Glycine residues have been reported to be associated with Alport syndrome, supporting the functional importance of this region of the protein (PMID: 24077912) (PM1). Functional studies have demonstrated that this variant significantly reduces COL4A5 protein and cell proliferation rate (PMID: 29142990) (PS3). This is a recurrence variant which has been previously reported multiple times in individuals with Alport syndrome (PMID: 17396119, 21332469, 24470729, 30691124, 31850286) and has been detected in three patients with Alport syndrome in our database (PS4). The variant is in dbSNP (rs104886142) and has been reported in population databases at low frequency (gnomAD 7/112356, 5 heterozygotes, 1 hemizygotes). The variant has been reported in ClinVar multiple times (Variation ID 24455) and HGMD (Accession CM983308) as pathogenic/ disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). Patient's phenotype and family history for this case is highly specific for the COL4A5 gene (PP4). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Apr 23, 2020 | This sequence change is predicted to replace glycine with aspartic acid at codon 624 of the COL4A5 protein (p.Gly624Asp). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the collagen triple helix domain but not in a full Gly-X-Y repeat. There is a moderate physicochemical difference between glycine and aspartic acid. The variant is present in a large population cohort at a frequency of 0.009% (rs104886142, 16/182,998 alleles, 0 homozygotes, 4 hemizygotes in gnomAD v2.1). The variant has been reported in association with haematuria, chronic renal failure, and end-stage renal disease with a later age of onset in both heterozygous females and hemizygous males, and segregates with disease in a large number of families (PMID: 17396119, 21332469, 24470729, 30691124, 31850286 - PP1_Strong). Additionally, a homozygote and a compound heterozygote female have been reported with X-linked Alport Syndrome (PMID: 31850286; SCV001150062.1 - PM3). A Dermal fibroblast cultures from a male hemizygote showed significantly reduced collagen IV alpha 5 chain protein expression and a reduced cell proliferation rate (PMID: 29142990 - PP4). The variant causes a secretion-dependent defect in an in vitro trimer formation assay (PMID: 29526710 - PS3_Supporting). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms - PP3). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PM3, PS3_Supporting, PP3, PP4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Diagnostic Laboratory, University of Szeged | Feb 02, 2016 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | Dec 21, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Dec 29, 2020 | The p.Gly624Asp variant in the COL4A5 gene has been previously reported in >20 unrelated individuals with Alport syndrome, thin basement membrane nephropathy, or benign familial hematuria and cosegregated with disease in >30 affected relatives from >10 families (Demosthenous et al., 2012; Frese et al., 2019; Kovács et al., 2016; Pierides et al., 2013; Šlajpah et al., 2007; Weber et al., 2016). Some studies reported this variant is associated with a milder phenotype (Demosthenous et al., 2012; Pierides et al, 2013). This variant has also been identified in 16/81,695 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Gly624Asp variant is located in a triple-helical region of COL4A5 that contains Gly-X-Y repeats. Other pathogenic missense variants impacting glycine residues have been described in this domain, which disrupt the function of COL4A5. Computational tools predict that the p.Gly624Asp variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Gly624Asp variant as pathogenic for X-linked Alport syndrome based on the information above. [ACMG evidence codes used: PS4; PM1; PM2; PP1_strong; PP3] - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 21, 2020 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 07, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jan 16, 2025 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 13, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 11, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 11, 2024 | Criteria applied: PS4,PM5_STR,PM1,PP3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 29, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Medical University of Lodz | Nov 29, 2024 | Alport syndrome 1, X-linked - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Aug 11, 2023 | This COL4A5 missense variant has been identified in several unrelated individuals as well as in families manifesting mild to severe features of COL4A5- related disease. This variant (rs104886142) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 16/182998 total alleles; 0.009%; 4 hemizygotes, no homozygotes). It has been reported in ClinVar (Variation ID 24455). Two bioinformatic tools queried predict that this substitution would be damaging, and the glycine residue at this position is evolutionarily conserved across most of the species assessed. We consider c.1871G>A in COL4A5 to be pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Aug 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 11, 2024 | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (33 heterozygotes, 0 homozygotes, 23 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional interruption of the triple helical domain (PMID: 21332469, PMID: 24470729). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several individuals with either Alport syndrome or benign familial haematuria. It is also described as a mild hypomorphic variant, explaining the phenotypic variability observed (VCGS internal cohort; ClinVar; PMID: 26809805). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | May 24, 2023 | This sequence variant is a single nucleotide substitution (G>A) which results in a glycine to aspartic acid amino acid change at residue 624 in the COL4A5 protein. This is a previously reported variant (ClinVar) which has been reported in heterozygous or hemizygous state in many individuals and families with Alport syndrome and/or hematuria (PMID: 9848783, 17396119, 19965530, 21332469, 24470729, 26934356, 33233744, 33309955); though this variant is typically associated with a mild form of Alport syndrome, it has been reported in homozygous state in a female with severe disease (PMID: 31850286). This variant is rare in the gnomAD control population dataset (16/182998 alleles or 0.009%). Multiple bioinformatic tools predict that this glycine to aspartic acid residue change will be damaging, and glycine is highly conserved at this position in vertebrates. Given the available evidence, we consider this variant to be pathogenic. ACMG Criteria: PP1, PP3, PP4, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PM1, PP2, PP3, PP4, PP5 - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2024 | Identified in some individuals with late-onset end stage renal disease, thin basement membrane nephropathy, and/or hematuria without additional clinical findings of Alport syndrome referred for genetic testing at GeneDx and in published literature (PMID: 9848783, 19965530, 21332469, 17396119, 24470729); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene; 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: 21332469, 30661074, 19965530, 29854973, 28844315, 30348286, 30586318, 33309955, 17396119, 11223851, 26809805, 24470729, 30691124, 26934356, 20378821, 19728970, 31850286, 33352548, 31754267, 34008892, 32359821, 33226606, 33233744, 33040356, 35675912, 35643372, 37012328, 9848783) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 08, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Aug 25, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 624 of the COL4A5 protein (p.Gly624Asp). This variant is present in population databases (rs104886142, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with a spectrum of COL4A5-related conditions which range from mild to severe and include benign familial hematuria, thin basement membrane nephropathy, late onset end stage renal disease, and Alport syndrome. (PMID: 17396119, 21332469, 21688191, 24470729, 26809805, 26934356, 29854973, 33309955). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24455). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A5 protein function. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | COL4A5: PM1:Strong, PM5, PS4:Moderate, PM2:Supporting, PP1, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 13, 2023 | PP1_strong, PP3, PP4, PM1, PS4 - |
Hypertensive disorder;C0268731:Glomerulopathy;C4022832:Mild proteinuria Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 13, 2015 | - - |
COL4A5-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 23, 2024 | The COL4A5 c.1871G>A variant is predicted to result in the amino acid substitution p.Gly624Asp. The p.Gly624 residue is located in the Gly-Xaa-Yaa triple helical domain (residues 42 – 1456 of the COL4A5 protein; uniprot.org). This variant has been reported in many individuals with COL4A5-related disorders and is typically associated with a milder clinical course (Martin et al. 1998. PubMed ID: 9848783; Slajpah et al. 2007. PubMed ID: 17396119; Macheroux et al. 2019. PubMed ID: 31850286; Frese et al. 2019. PubMed ID: 30691124; Żurowska et al. 2020. PubMed ID: 33309955). The c.1871G>A is also reported as a founder variant in individuals from Central and East Europe (Żurowska et al. 2020. PubMed ID: 33309955). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Alport syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Jan 31, 2015 | 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). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;T
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;T;.
Sift4G
Uncertain
D;T;.
Polyphen
1.0
.;D;D
Vest4
MVP
MPC
ClinPred
T
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RBP_binding_hub_radar
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at