rs104886308

chrX-108696350-G-AchrX-108696350-G-CchrX-108696350-G-T

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.5048G>A(p.Arg1683Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,095,246 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1683R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 10.0

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 strand (size 6) in uniprot entity CO4A5_HUMAN there are 5 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, 0.986
• PP5: Variant X-108696350-G-A is Pathogenic according to our data. Variant chrX-108696350-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108696350-G-A is described in Lovd as [Pathogenic]. Variant chrX-108696350-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.5048G>A	p.Arg1683Gln	missense_variant	53/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.5048G>A	p.Arg1683Gln	missense_variant	53/53	1	NM_033380.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000218 AC: 4 AN: 183310 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1095246 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 360768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Alport syndrome Pathogenic:7 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 20, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Feb 13, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: COL4A5 c.5030G>A (p.Arg1677Gln) results in a conservative amino acid change located in the Collagen IV, non-collagenous domain of the encoded protein sequence. 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 2.2e-05 in 183310 control chromosomes. c.5030G>A has been reported in the literature in multiple individuals affected with Alport Syndrome 1, X-Linked Recessive or Nephrosclerosis/deafness (e.g. Bekheirnia_2010, Ottlewski_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, 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 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, PMID: 12028435). (I) 0110 - This gene is known to be 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 arginine to glutamine. (I) 0253 - Variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the C-terminal tandem repeated domain in type 4 collagen (NCBI conserved domain). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Arg1677Pro) and p.(Arg1677Leu) comparable variants have each been reported in an individual with Alport Syndrome, respectively (PMIDs: 11223851; 21505094). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is an Ashkenazi Jewish founder mutation and has been classified as pathogenic in ClinVar (PMIDs: 9150741; 27627812). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. HEK293T cells carrying the p.(Arg1683Gln) mutant construct demonstrated impaired trimer formation ability with alpha-3 and alpha-4 collagen chains compared with the wild type construct (PMID: 29526710). (SP) 1102 - Strong phenotype match. (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 06, 2022	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2021	Published functional studies demonstrate R1683Q results in a loss of formation of the type IV collagen heterotrimers (Kobayashi et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19919694, 20378821, 9150741, 29144512, 29204651, 29526710, 18083113) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1677 of the COL4A5 protein (p.Arg1677Gln). This variant is present in population databases (rs104886308, gnomAD 0.04%). This missense change has been observed in individuals with adult-onset Alport syndrome (PMID: 9150741, 19919694, 20378821). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10467). 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. Experimental studies have shown that this missense change affects COL4A5 function (PMID: 18083113). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 11, 2018	Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Damaging to protein function(s) relevant to disease mechanism. -

COL4A5-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2024

The COL4A5 c.5030G>A variant is predicted to result in the amino acid substitution p.Arg1677Gln. This variant was reported in three independent Ashkenazi-American families with features of COL4A5-related disorders (Barker et al. 1997. PubMed ID: 9150741; Pont-Kingdon et al. 2009. PubMed ID: 19919694). This variant was also reported in a 57 year old female patient with mild chronic kidney disease (Table 2 in Lata et al. 2017. PubMed ID: 29204651) and in a male patient with nephrosclerosis and deafness and his mother with deafness (Ottlewski et al. 2019. PubMed ID: 31027891). This variant is reported in 0.040% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -

Hematuria Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

May 30, 2018

This patient is heterozygous for a known pathogenic variant, c.5030G>A (p.Arg1677Gln), in the COL4A5 gene. This variant (dbSNP: rs104886308), located in the C terminal domain of COL4A5, has been previously reported in numerous patients with adult-onset X-linked Alport syndrome in the literature (Barker et al 1997 Hum Genet 99:681-684; Pont-Kingdon et al 2009 BMC Nephrol 10:38; Bekheirnia et al 2010 J Am Soc Nephrol 21:876-883). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.90
MutPred		0.95		.;Loss of MoRF binding (P = 0.0268);
MVP		0.99
MPC		1.1
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.96

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: rs104886308; hg19: chrX-107939580; COSMIC: COSV60366574;