rs104886308

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_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 (★★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 0 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 10.0

Variant links:

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]

COL4A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) 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 rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.5048G>A	p.Arg1683Gln	missense_variant	Exon 53 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 link	c.5048G>A	p.Arg1683Gln	missense_variant	Exon 53 of 53	1	NM_033380.3	ENSP00000331902.7		P29400-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183310

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67786

show subpopulations

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:

AN:

1095246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360768

show subpopulations

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.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Pathogenic:8Other:1

Oct 20, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2019

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 22, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010467 /PMID: 9150741). Different missense changes at the same codon (p.Arg1683Leu, p.Arg1683Pro) have been reported to be associated with COL4A5 related disorder (PMID: 11223851, 21505094). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 30, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided

Pathogenic:5

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 11, 2018

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence 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 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. -

Nov 03, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PS4 -

Nov 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate p.(R1683Q) results in a loss of formation of the type IV collagen heterotrimers (PMID: 18083113); 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: 29144512, 30586318, 31027891, 37895203, 37547535, 29526710, 29204651, 9150741, 20378821, 19919694, 35643372, 18083113) -

COL4A5-related disorder

Pathogenic:1

Feb 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

May 30, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.80

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

.;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

.;M

PrimateAI

Uncertain

0.77

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over