rs104886303

chrX-108695409-T-G

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.4964T>G(p.Leu1655Arg) variant causes a missense change involving the alteration of a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L1655L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 8.02

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 disulfide_bond Or C-1586 with C-1678 (size 95) in uniprot entity CO4A5_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-108695409-T-G is Pathogenic according to our data. Variant chrX-108695409-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 10466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108695409-T-G is described in Lovd as [Pathogenic]. Variant chrX-108695409-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.4964T>G	p.Leu1655Arg	missense_variant	52/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.4964T>G	p.Leu1655Arg	missense_variant	52/53	1	NM_033380.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00000993 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Alport syndrome Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 24, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1996	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2021	The COL4A5 c.4946T>G; p.Leu1649Arg variant (rs104886303), also reported as Leu1655Arg, has been described in multiple individuals and families affected with Alport syndrome and is associated with a mild phenotype presenting in adulthood (Barker 1996, Barker 2001, Kobayashi 2008, Martin 1998, Pont-Kingdon 2009). It is reported as pathogenic by multiple sources in ClinVar (Variation ID: 10466), and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 1649 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In agreement with this, in vitro analysis of the variant protein demonstrates defective trimerization, leading to secretion of a less stable monomeric alpha chain (Kobayashi 2008). Based on available information, this variant is considered pathogenic. REFERENCES Barker D et al. A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. Am J Hum Genet. 1996 Jun;58(6):1157-65. Barker D et al. Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. Am J Med Genet. 2001 Jan 15;98(2):148-60. Kobayashi T et al. Mutational analysis of type IV collagen alpha5 chain, with respect to heterotrimer formation. Biochem Biophys Res Commun. 2008 Feb 1;366(1):60-5. 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. Pont-Kingdon G et al. Molecular testing for adult type Alport syndrome. BMC Nephrol. 2009 Nov 17;10:38. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1649 of the COL4A5 protein (p.Leu1649Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 8651292, 23572034). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10466). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL4A5 function (PMID: 18083113). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.5148T>G, p.L1649R. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. Introduction of this variant into the mouse homologue resulted in defective formation of the collagen heterotrimer (PMID: 18083113). Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 25, 2022	PP3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Also known as p.(L1649R) due to alternative nomenclature; Individuals previously reported with this variant were noted to have relatively mild Alport syndrome with onset in the 4th or 5th decade, with late hearing loss approximately 10 years after the onset of renal failure (Barker et al, 1996); This variant is associated with the following publications: (PMID: 17396119, 24470729, 19919694, 20301386, 18083113, 8651292, 27627812, 30647093, 23572034, 11223851, 9848783) -

COL4A5-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2023

The COL4A5 c.4946T>G variant is predicted to result in the amino acid substitution p.Leu1649Arg. This variant has been reported in several individuals with Alport syndrome (Barker et al. 1996. PubMed ID: 8651292; Pont-Kingdon et al. 2009. PubMed ID: 19919694; Yao et al. 2019. PubMed ID: 30647093). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. The c.4946T>G variant is reported in Clinvar as pathogenic by many outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/10466). This variant is interpreted as pathogenic. -

Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
Cadd	Pathogenic	27
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.94		.;Loss of stability (P = 0.0081);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104886303; hg19: chrX-107938639;