rs1555300086

Variant names:

• chr13-110150392-G-A
• rs1555300086
• NM_001845.6:c.4981C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001845.6(COL4A1):​c.4981C>T​(p.Arg1661Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1661H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.55
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 13-110150392-G-A is Pathogenic according to our data. Variant chr13-110150392-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521435.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.4981C>T	p.Arg1661Cys	missense_variant	Exon 52 of 52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.4981C>T	p.Arg1661Cys	missense_variant	Exon 52 of 52	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

May 04, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_MOD, PS4_SUP, PM2_SUP, PP2, PP3 -

Inborn genetic diseases Pathogenic:1

Jul 25, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4981C>T (p.R1661C) alteration is located in exon 52 (coding exon 52) of the COL4A1 gene. This alteration results from a C to T substitution at nucleotide position 4981, causing the arginine (R) at amino acid position 1661 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in one individual in an fetal intracranial hemorrhage cohort but clinical details were limited (Coste, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Uncertain:1

Sep 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 521435). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1661 of the COL4A1 protein (p.Arg1661Cys). -

COL4A1 or COL4A2-related cerebral small vessel disease Uncertain:1

-

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant is absent from gnomAD (both v2 and v3). - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). Additional information: - Dominant negative and loss of function are likely mechanisms of disease in this gene and are associated with COL4A1-related disorders. Missense variants affecting the glycine of the triple helix of collagen protiens typically exert a dominant-negative effect however, functional studies for this gene are currently lacking (PMID: 16159887). - This gene is associated with autosomal dominant disease. - The condition associated with this gene has incomplete penetrance (PMID: 30413629, PMID:21625620). - Variant is predicted to result in a missense amino acid change from arginine to cysteine. - This variant is heterozygous. - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). - Variant is located in the annotated C4 domain (DECIPHER). - No comparable missense variants have previous evidence for pathogenicity. - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS in an individual with features including seizures, microcephaly and oligohydramnios (ClinVar). - No published segregation evidence has been identified for this variant. - No published functional evidence has been identified for this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.78		Gain of catalytic residue at R1656 (P = 0);
MVP		0.95
MPC		0.53
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.88
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs1555300086; hg19: chr13-110802739;