13-110179298-C-T

Variant names:

• chr13-110179298-C-T
• rs672601347
• NM_001845.6:c.2317G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1 PM2 PP3_Strong PP5_Very_Strong

The NM_001845.6(COL4A1):​c.2317G>A​(p.Gly773Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.86
• Publications: 10 publications found

Genes affected

COL4A1 (HGNC:2202): (collagen type IV alpha 1 chain) This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

COL4A1 Gene-Disease associations (from GenCC):

• brain small vessel disease 1 with or without ocular anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• microangiopathy and leukoencephalopathy, pontine, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontine autosomal dominant microangiopathy with leukoencephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinal arterial tortuosity

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PS1: Transcript NM_001845.6 (COL4A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 13-110179298-C-T is Pathogenic according to our data. Variant chr13-110179298-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 379845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001845.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.2317G>A	p.Gly773Arg	missense	Exon 30 of 52	NP_001836.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.2317G>A	p.Gly773Arg	missense	Exon 30 of 52	ENSP00000364979.4
	COL4A1	ENST00000650424.2		c.2317G>A	p.Gly773Arg	missense	Exon 30 of 52	ENSP00000497477.2
	COL4A1	ENST00000615732.3	TSL:5	c.2125G>A	p.Gly709Arg	missense	Exon 30 of 52	ENSP00000478222.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brain small vessel disease 1 with or without ocular anomalies Pathogenic:3

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.87). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000379845). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25457163 , 33527515). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22574627 , 24374867 , 24628545 , 25457163 , 31051113 , 33353976 , 33527515). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.2317G>A (p.Gly773Arg) variant in COL4A1 gene has been reported in multiple individuals affected with COL4A1-related disorders (Shah et al., 2012; Colin et al., 2014; Deml et al., 2014; Slavotinek et al., 2015; Labelle-Dumais et al., 2019; Hausman-Kedem et al., 2021). This variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Gly773Arg in COL4A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 773 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

Jul 28, 2023

Molecular Medicine, University of Pavia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not provided Pathogenic:3

Nov 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Affects a glycine residue in a Gly-X-Y motif in the triple-helical region of the COL4A1 gene, where the majority of pathogenic missense variants occur and is predicted to disrupt normal protein folding and function (HGMD); Not observed in large population cohorts (gnomAD); 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: 25457163, 28098148, 24628545, 30837194, 31051113, 33527515, 31848469, 16107487, 17938367, 23394911)

Mar 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 773 of the COL4A1 protein (p.Gly773Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with COL4A1-related conditions (PMID: 22574627, 25457163, 33527515). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 379845). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant disrupts the triple helix domain of COL4A1. 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 COL4A1 variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL4A1-related disorder Pathogenic:1

May 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL4A1 c.2317G>A variant is predicted to result in the amino acid substitution p.Gly773Arg. This variant has been reported de novo in multiple individuals with clinical features consistent with COL4A1-related disorders (Deml et al. 2014. PubMed ID: 24628545; Slavotinek et al. 2015. PubMed ID: 25457163; Hausman-Kedem et al. 2021. PubMed ID: 33527515; Lenassi et al. 2021. PubMed ID: 31848469; PreventionGenetics, internal data). The p.Gly348Asp variant affects a glycine residue in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (Zagaglia et al. 2018. PubMed ID: 30413629). This variant has not been reported in a large population database, indicating this variant is rare and has been consistently interpreted as pathogenic and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/379845/). Taken together, this variant is interpreted as pathogenic.

Inborn genetic diseases Pathogenic:1

Aug 10, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2317G>A (p.G773R) alteration is located in coding exon 30 of the COL4A1 gene. This alteration results from a G to A substitution at nucleotide position 2317, causing the glycine (G) at amino acid position 773 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation and has been reported as heterozygous in multiple individuals with features consistent with COL4A1-related disorder (Deml, 2014; Colin, 2014; Slavotinek, 2015; Hausman-Kedem, 2021). Another alteration that causes the same amino acid change c.2317G>C (p.G773R) has also been detected in two related individuals with clinical features consistent with COL4A1-related disorder (Shah, 2012). This amino acid position is highly conserved in available vertebrate species. The p.G773 amino acid is located within the triple-helical domain of the collagen IV alpha 1 chain, and this alteration affects one of the highly conserved glycine residues in the Gly-X-Y motif that make up this domain (Ramshaw, 1998). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Retinal arterial tortuosity;C2673195:Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome;C3281105:Hemorrhage, intracerebral, susceptibility to;C4551998:Brain small vessel disease 1 with or without ocular anomalies;C5231411:Microangiopathy and leukoencephalopathy, pontine, autosomal dominant Pathogenic:1

Jul 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		6.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.88		Gain of catalytic residue at P774 (P = 0)
MVP		0.99
MPC		0.59
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.89
gMVP		1.0
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs672601347; hg19: chr13-110831645; COSMIC: COSV101011529;