chr1-102888730-C-A

Position:

• chr1-102888730-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000370096.9(COL11A1):​c.4547G>T​(p.Gly1516Val) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1516D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL11A1 ENST00000370096.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91

Genes affected

COL11A1 (HGNC:2186): (collagen type XI alpha 1 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Mutations in this gene are associated with type II Stickler syndrome and with Marshall syndrome. A single-nucleotide polymorphism in this gene is also associated with susceptibility to lumbar disc herniation. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000370096.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-102888730-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3366881.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 1-102888730-C-A is Pathogenic according to our data. Variant chr1-102888730-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 498797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-102888730-C-A is described in Lovd as [Likely_pathogenic]. Variant chr1-102888730-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.4547G>T	p.Gly1516Val	missense_variant	61/67	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.4547G>T	p.Gly1516Val	missense_variant	61/67	1	NM_001854.4	ENSP00000359114	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marshall syndrome;C1858084:Stickler syndrome type 2;C4760307:Hearing loss, autosomal dominant 37 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Sep 11, 2020

- -

COL11A1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2024

The COL11A1 c.4547G>T variant is predicted to result in the amino acid substitution p.Gly1516Val. This variant has been reported in two individuals with Marshall/Stickler syndrome/isolated hearing loss (reported as G988V; Annunen et al. 1999. PubMed ID: 10486316; reported as de novo, Van Heurck et al. 2021. PubMed ID: 34440452). This variant affects a Gly residue of the conserved Gly-Xaa-Yaa triple helical domain (amino acid residues 529-1542, www.uniprot.org/uniprotkb/P12107/), where substitutions of glycine are usually pathogenic (Richards et al. 2010. PubMed ID: 20513134; https://www.ncbi.nlm.nih.gov/books/NBK1302/). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

Marshall syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Nov 09, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 23, 2018

- -

Stickler syndrome type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Feb 05, 2022

The c.4547G>T;p.(Gly1516Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 20513134) - PS4_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (collagen helix of α1(XI) collagen) - PM1. This variant is not present in population databases (rs1553193910; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.5	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	1.0
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.97
MutPred		0.99		Loss of glycosylation at K1515 (P = 0.0956);.;.;.;
MVP		0.99
MPC		0.15
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553193910; hg19: chr1-103354286; COSMIC: COSV100618500; COSMIC: COSV100618500;