chr1-102888730-C-A

Variant names:

• chr1-102888730-C-A
• rs1553193910
• NM_001854.4:c.4547G>T

Variant summary

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

The NM_001854.4(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 NM_001854.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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, 9 uncertain in NM_001854.4
• 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 rank	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.4547G>T	p.Gly1516Val	missense_variant	Exon 61 of 67	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.4547G>T	p.Gly1516Val	missense_variant	Exon 61 of 67	1	NM_001854.4	ENSP00000359114.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 23, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 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 valine, which is neutral and non-polar, at codon 1516 of the COL11A1 protein (p.Gly1516Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Stickler syndrome (PMID: 10486316, 20513134; Invitae). This variant is also known as G988V. ClinVar contains an entry for this variant (Variation ID: 498797). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL11A1 protein function. For these reasons, this variant has been classified as Pathogenic. -

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

Sep 11, 2020

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL11A1-related disorder Pathogenic:1

Apr 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Nov 09, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stickler syndrome type 2 Pathogenic:1

Feb 05, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.
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;