X-108580548-C-T

Variant names:

• chrX-108580548-C-T
• rs104886071
• NM_033380.3:c.796C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.796C>T​(p.Arg266*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.18
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108580548-C-T is Pathogenic according to our data. Variant chrX-108580548-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 24325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.796C>T	p.Arg266*	stop_gained	Exon 14 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.796C>T	p.Arg266*	stop_gained	Exon 14 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.796C>T	p.Arg266*	stop_gained	Exon 14 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00249 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg266*) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 15780079, 17396119, 29854973). ClinVar contains an entry for this variant (Variation ID: 24325). For these reasons, this variant has been classified as Pathogenic. -

Jul 20, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15780079, 25525159, 15954103, 17396119) -

X-linked Alport syndrome Pathogenic:3

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL4A5 c.796C>T; p.Arg266Ter variant (rs104886071) is reported in the literature in several heterozygous and hemizygous individuals with symptoms of Alport syndrome (Gillion 2018, Kim 2023, Mastrangelo 2020, Nagel 2005, Rao 2019, Slajpah 2007, Wang 2005). This variant is reported as pathogenic in ClinVar (Variation ID: 24325). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Gillion V et al. Genotype and Outcome After Kidney Transplantation in Alport Syndrome. Kidney Int Rep. 2018 Feb 2;3(3):652-660. PMID: 29854973. Kim JH et al. Genotype-phenotype correlation of X-linked Alport syndrome observed in both genders: a multicenter study in South Korea. Sci Rep. 2023 Apr 26;13(1):6827. PMID: 37100867. Mastrangelo A et al. X-Linked Alport Syndrome in Women: Genotype and Clinical Course in 24 Cases. Front Med (Lausanne). 2020 Nov 23;7:580376. PMID: 33330536. Nagel M et al. Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome. Hum Mutat. 2005 Jul;26(1):60. PMID: 15954103. Rao J et al. Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system. Clin Genet. 2019 Nov;96(5):402-410. PMID: 31328266. 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. PMID: 17396119. Wang F et al. Detection of mutations in the COL4A5 gene by analyzing cDNA of skin fibroblasts. Kidney Int. 2005 Apr;67(4):1268-74. PMID: 15780079. -

Alport syndrome Pathogenic:1

Sep 10, 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.796C>T, in the COL4A5 gene. This variant (dbSNP: rs104886071) creates a premature stop codon (p.Arg266*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been previously reported in the COL4A5 Alport database (http://www.arup.utah.edu/database/ALPORT/ALPORT_welcome.php) and is considered to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.75	D
PhyloP100		2.2
Vest4		0.90
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs104886071; hg19: chrX-107823778;