NM_080680.3:c.1861C>A

Variant names:

• chr6-33178143-G-T
• rs121912952
• NM_080680.3:c.1861C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BS1_Supporting

The NM_080680.3(COL11A2):​c.1861C>A​(p.Pro621Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000888 in 1,609,686 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (1 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5
• Conservation: PhyloP100: 1.03
• Publications: 14 publications found

Genes affected

COL11A2 (HGNC:2187): (collagen type XI alpha 2 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. It is located on chromosome 6 very close to but separate from the gene for retinoid X receptor beta. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Proteolytic processing of this type XI chain produces PARP, a proline/arginine-rich protein that is an amino terminal domain. Mutations in this gene are associated with type III Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED syndrome), Weissenbacher-Zweymuller syndrome, autosomal dominant non-syndromic sensorineural type 13 deafness (DFNA13), and autosomal recessive non-syndromic sensorineural type 53 deafness (DFNB53). Alternative splicing results in multiple transcript variants. A related pseudogene is located nearby on chromosome 6. [provided by RefSeq, Jul 2009]

COL11A2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 13

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• otospondylomegaepiphyseal dysplasia, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive nonsyndromic hearing loss 53

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• otospondylomegaepiphyseal dysplasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• otospondylomegaepiphyseal dysplasia, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fibrochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 6-33178143-G-T is Pathogenic according to our data. Variant chr6-33178143-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17129.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000926 (135/1457818) while in subpopulation MID AF = 0.000696 (4/5750). AF 95% confidence interval is 0.000422. There are 1 homozygotes in GnomAdExome4. There are 73 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080680.3. 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
	COL11A2	NM_080680.3	MANE Select	c.1861C>A	p.Pro621Thr	missense	Exon 21 of 66	NP_542411.2
	COL11A2	NM_001424108.1		c.1681C>A	p.Pro561Thr	missense	Exon 20 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.1603C>A	p.Pro535Thr	missense	Exon 19 of 64	NP_542412.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.1861C>A	p.Pro621Thr	missense	Exon 21 of 66	ENSP00000339915.2
	COL11A2	ENST00000374708.8	TSL:5	c.1603C>A	p.Pro535Thr	missense	Exon 19 of 64	ENSP00000363840.4
	COL11A2	ENST00000361917.6	TSL:5	c.444+165C>A		intron	N/A	ENSP00000355123.2

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151868 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000899 AC: 22 AN: 244724 AF XY: 0.000135

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000819

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000926 AC: 135 AN: 1457818 Hom.: 1 Cov.: 34 AF XY: 0.000101 AC XY: 73 AN XY: 724838

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.000547 AC: 47 AN: 85962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52294

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 0.0000676 AC: 75 AN: 1110038

Other (OTH) AF: 0.000149 AC: 9 AN: 60230

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151868 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74168

African (AFR) AF: 0.00 AC: 0 AN: 41324

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000135 AC: 16

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 621 of the COL11A2 protein (p.Pro621Thr). This variant is present in population databases (rs121912952, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 16033917). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17129). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL11A2 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL11A2: PP1:Strong, PM2

Aug 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the homozygous state in five relatives from a consanguineous family with non-syndromic hearing loss (PMID: 16033917); 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: 34426522, 16033917)

Autosomal recessive nonsyndromic hearing loss 53 Pathogenic:1 Uncertain:1

Oct 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 01, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Otospondylomegaepiphyseal dysplasia, autosomal dominant;C1864746:Autosomal recessive nonsyndromic hearing loss 53;C1866095:Autosomal dominant nonsyndromic hearing loss 13;C3281128:Fibrochondrogenesis 2;C5551484:Otospondylomegaepiphyseal dysplasia, autosomal recessive Pathogenic:1

Apr 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Mar 08, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro621Thr variant in COL11A2 has been reported in the homozygous state in one Iranian ind ividual with hearing loss and segregated with disease in 4 affected relatives wi thin the individual's consanguineous family (Chen 2005). This variant has also b een identified in 10/14172 South Asian chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121912952). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that the p.Pro621Thr variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. However, there is limited data associating variants in the COL11A2 gene wit h autosomal recessive nonsyndromic hearing loss. Only three consanguineous famil ies with homozygous variants in COL11A2 have been described, including the famil y described above with the p.Pro621THr variant. In addition, there is limited da ta of the general populations from which these families are from (Iranian, Tunis ian, and Turkish; Chen 2005, Chakchouk 2015). In summary, although there is some suspicion for a pathogenic role, the clinical significance of this variant is u ncertain.

Hearing impairment Uncertain:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1_Moderate, PM2_Moderate

Fibrochondrogenesis 2 Uncertain:1

Sep 24, 2024

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous variant in exon 21 of the COL11A2 gene that results in the amino acid substitution of Threonine for Prolin at codon 621 was detected. The observed variant c.1861C>A (p.Pro621Thr) has not found in the 1000 genomes and has minor allele frequency of 0.008% and 0.005% in the gnomAD (V2.1) and gnomAD (V3.1) databases respectively. The in silico prediction of the variant is probably damaging by PolyPhen-2, SIFT, LRT and MutationTaster2. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.75	D
PhyloP100		1.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.73
Sift	Benign	0.091	T
Sift4G	Uncertain	0.058	T
Vest4		0.52
MutPred		0.73		Gain of phosphorylation at P621 (P = 0.0056)
MVP		0.93
MPC		0.99
ClinPred		0.26	T
GERP RS		4.3
gMVP		0.41
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912952; hg19: chr6-33145920; COSMIC: COSV59500310; COSMIC: COSV59500310;