rs104886189

Positions:

• chrX-108620354-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):​c.2605G>A​(p.Gly869Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,642 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a compositionally_biased_region Pro residues (size 31) in uniprot entity CO4A5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant X-108620354-G-A is Pathogenic according to our data. Variant chrX-108620354-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108620354-G-A is described in Lovd as [Pathogenic]. Variant chrX-108620354-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2605G>A	p.Gly869Arg	missense_variant	31/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2605G>A	p.Gly869Arg	missense_variant	31/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1429G>A	p.Gly477Arg	missense_variant	15/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2605G>A	p.Gly869Arg	missense_variant	31/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095642 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Alport syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000024543, PS1_S). A different missense change at the same codon has been reported to be associated with COL4A5 related disorder (ClinVar ID: VCV000807394, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.978, 3CNET: 0.973, PP3_P). A missense variant is a common mechanism associated with Alport syndrome 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Dec 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 23, 2024	Variant summary: COL4A5 c.2605G>A (p.Gly869Arg) results in a non-conservative amino acid change located within the triple-helical region (UniProt) of the encoded protein sequence. This missense variant disrupts a critical glycine residue at position 1 of a Gly-X-Y repeat in the collagenous domain of the collagen IV alpha 5 chain, and variants affecting these glycine residues are significantly enriched in individuals with Alport syndrome (PMID: 33854215). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182139 control chromosomes. c.2605G>A has been reported in the literature in individuals affected with Alport Syndrome 1, X-Linked Recessive (example, Connaughton_2019, Hashimura_2014, Ma_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30773290, 24304881, 21505094). ClinVar contains an entry for this variant (Variation ID: 24543). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Watson Genetic Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, caused by missense variants mostly glycine substitutions that affect the conformation of the protein, and loss of function, caused by either protein truncating or missense variants, are known mechanisms of disease in this gene and are associated with Alport syndrome (MIM#301050) (PMIDs: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease, with males usually affected more severely 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 arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (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 triple helical G-X-Y repeat region, and affects a glycine residue (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly869Val) has been previously reported as pathogenic by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and has been observed in many hemizygous or heterozygous individuals with Alport syndrome (ClinVar, PMIDs: 27627812, 23144074). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The hemizygous p.Gly869Arg variant in COL4A5 was identified by our study in one individual with X-linked Alport syndrome. This variant was absent from large population studies and computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Trio exome analysis showed this variant to be de novo in one individual reported in the literature (PMID: 8940267). The p.Gly869Arg variant in COL4A5 has been reported in ten additional individuals with Alport syndrome (PMID: 8651296, 7599631, 9848783). This variant has also been reported pathogenic in ClinVar (Variation ID: 24543). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM6, PP3 (Richards 2015). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). 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 COL4A5 protein function. ClinVar contains an entry for this variant (Variation ID: 24543). This variant is also known as c.2808G>A. This missense change has been observed in individuals with Alport syndrome (PMID: 7599631, 30577881). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 869 of the COL4A5 protein (p.Gly869Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2016	The G869R pathogenic variant in the COL4A5 gene has been reported previously in multiple unrelated individuals with X-linked Alport syndrome (Boye et al., 1995; Knebelman et al., 1996; Plant et al., 1999). The G869R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G869R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G869R as a pathogenic variant. -

Alport syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Sep 13, 2019

This individual is heterozygous for the c.2605G>A variant in the COL4A5 gene, which results in the amino acid substitution of glycine to arginine at residue 869, p.(Gly869Arg). This substitution affects one of the invariant glycine residues within the triple helical domain. This variant has been reported in numerous individuals with Alport syndrome (Knebelmann B et al 1996 Am J Hum Genet 59: 1221-1232; Ma et al 2011 Nephrol Dial Transplant 26: 4003-4010; Strasser et al 2012 Nephrol Dial Transplant 27: 4236-4240; Alport (COL4A5) Database: http://www.arup.utah.edu/database/ALPORT/ALPORT_display.php). The c.2605G>A variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PM1_Strong, PS4). -

Autosomal dominant Alport syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Feb 14, 2019

- -

Atypical hemolytic-uremic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Oct 25, 2018

This patient is hemizygous for the c.2605G>A (p.Gly869Arg) variant in the COL4A5 gene. This variant has been reported to be associated with Alport syndrome (Strasser et al Nephrol Dial Transplant (2012) 27: 4236-4240). In silico analysis (Alamutv2.4) using Align GVGD, PolyPhen2, SIFT and Mutation taster all predict that this variant is likely to be pathogenic. In addition, p.Gly869 is a highly conserved amino acid within the triple helix domain. Glycine residues, in this domain, are important for the steric arrangement of the collagen chains (Knebelmann B et al. Am J Hum Genet 1996; 59: 1221-1232). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.8	H;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.0	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		1.0
MutPred		1.0		Gain of methylation at G869 (P = 0.0253);Gain of methylation at G869 (P = 0.0253);.;
MVP		1.0
MPC		0.36
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104886189; hg19: chrX-107863584; COSMIC: COSV60360372; COSMIC: COSV60360372;