13-110179298-C-T

Position:

• chr13-110179298-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM2 PP2 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin 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:6
• Conservation: PhyloP100: 6.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_001845.6 (COL4A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 161975
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, COL4A1
• 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 [Likely_pathogenic]. Clinvar id is 379845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110179298-C-T is described in Lovd as [Pathogenic]. Variant chr13-110179298-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.2317G>A	p.Gly773Arg	missense_variant	30/52	ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.2317G>A	p.Gly773Arg	missense_variant	30/52	1	NM_001845.6	P1
COL4A1	ENST00000649738.1	n.2447G>A		non_coding_transcript_exon_variant	30/31

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brain small vessel disease 1 with or without ocular anomalies Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -
Likely pathogenic, criteria provided, single submitter	research	Molecular Medicine, University of Pavia	Jul 28, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs672601347; hg19: chr13-110831645; COSMIC: COSV101011529;