NM_080680.3(COL11A2):c.966dup (p.Thr323fs) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000592394.17

Allele description

NM_080680.3(COL11A2):c.966dup (p.Thr323fs)

Gene:

COL11A2:collagen type XI alpha 2 chain [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

6p21.32

Genomic location:

Preferred name:

NM_080680.3(COL11A2):c.966dup (p.Thr323fs)

Other names:

p.Thr323HisfsTer19

HGVS:

NC_000006.12:g.33184297_33184298insG
NC_000006.12:g.33184304dup
NG_011589.1:g.13171dup
NM_080679.3:c.798+2329dup
NM_080680.3:c.966dupMANE SELECT
NM_080681.3:c.861+694dup
NP_542411.2:p.Thr323fs
NC_000006.11:g.33152074_33152075insG
NC_000006.11:g.33152081dup
NM_080680.2:c.966dup
NM_080680.2:c.966dupC
NM_080680.3:c.966dupCMANE SELECT

Protein change:

T323fs

Links:

dbSNP: rs748440351

NCBI 1000 Genomes Browser:

rs748440351

Molecular consequence:

NM_080680.3:c.966dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_080679.3:c.798+2329dup - intron variant - [Sequence Ontology: SO:0001627]
NM_080681.3:c.861+694dup - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

mutation affecting reading frame [Sequence Ontology: SO:1000064]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000702400	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Oct 6, 2016)	germline	clinical testing	Citation Link,
SCV001167938	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 17, 2023)	germline	clinical testing	Citation Link,
SCV001959051	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001973397	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002023276	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 25, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002233340	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10677296, 21204229, 29456477, 31299979, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene.

Melkoniemi M, Brunner HG, Manouvrier S, Hennekam R, Superti-Furga A, Kääriäinen H, Pauli RM, van Essen T, Warman ML, Bonaventure J, Miny P, Ala-Kokko L.

Am J Hum Genet. 2000 Feb;66(2):368-77.

PubMed [citation]

PMID:: 10677296
PMCID:: PMC1288089

See all PubMed Citations (6)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000702400.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneDx, SCV001167938.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29456477, 26445815, 31299979, 31980526, 34265623, 31850270, 33597575, 36056583)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959051.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001973397.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002023276.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002233340.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Thr323Hisfs*19) in the COL11A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL11A2 are known to be pathogenic (PMID: 10677296, 21204229). This variant is present in population databases (rs748440351, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive COL11A2-related conditions (PMID: 29456477, 31299979). ClinVar contains an entry for this variant (Variation ID: 497724). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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