NM_001844.5(COL2A1):c.905C>T (p.Ala302Val) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 28, 2023
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:: RCV000518971.15

Allele description [Variation Report for NM_001844.5(COL2A1):c.905C>T (p.Ala302Val)]

NM_001844.5(COL2A1):c.905C>T (p.Ala302Val)

Gene:

COL2A1:collagen type II alpha 1 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.11

Genomic location:

Preferred name:

NM_001844.5(COL2A1):c.905C>T (p.Ala302Val)

HGVS:

NC_000012.12:g.47993828G>A
NG_008072.1:g.15675C>T
NM_001844.5:c.905C>TMANE SELECT
NM_033150.3:c.698C>T
NP_001835.3:p.Ala302Val
NP_149162.2:p.Ala233Val
NC_000012.11:g.48387611G>A
NM_001844.4:c.905C>T

Protein change:

A233V

Links:

dbSNP: rs1555168505

NCBI 1000 Genomes Browser:

rs1555168505

Molecular consequence:

NM_001844.5:c.905C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033150.3:c.698C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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SRP137300 (1)
SRA
DNA topoisomerase (ATP-hydrolyzing) subunit B [Mycoplasmoides pneumoniae]
DNA topoisomerase (ATP-hydrolyzing) subunit B [Mycoplasmoides pneumoniae]
gi|499176773|ref|WP_010874360.1|

Protein
Financing, Organized
Financing, Organized
All organized methods of funding.<br/>Year introduced: 1968

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000616681	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 16, 2022)	germline	clinical testing	Citation Link,
SCV002240369	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 28, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 17347327, 25604898, 26037341, 7977371, 8893763, 7695699, 8218237, 19344236, 9016532, 17078022, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000616681

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 16, 2022)

germline

clinical testing

Citation Link,

SCV002240369

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 28, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Significant ocular findings are a feature of heritable bone dysplasias resulting from defects in type II collagen.

Meredith SP, Richards AJ, Bearcroft P, Pouson AV, Snead MP.

Br J Ophthalmol. 2007 Sep;91(9):1148-51. Epub 2007 Mar 8.

PubMed [citation]

PMID:: 17347327
PMCID:: PMC1954906

A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype.

Terhal PA, Nievelstein RJ, Verver EJ, Topsakal V, van Dommelen P, Hoornaert K, Le Merrer M, Zankl A, Simon ME, Smithson SF, Marcelis C, Kerr B, Clayton-Smith J, Kinning E, Mansour S, Elmslie F, Goodwin L, van der Hout AH, Veenstra-Knol HE, Herkert JC, Lund AM, Hennekam RC, et al.

Am J Med Genet A. 2015 Mar;167A(3):461-75. doi: 10.1002/ajmg.a.36922. Epub 2015 Jan 21.

PubMed [citation]

PMID:: 25604898

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000616681.4

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

Description

Observed in patients with type II collagenopathies in published literature (Bogaert R, et al., 1994; Chen et al., 1996; Terhal et al., 2015).; Functional studies show the variant results in a cryptic splice donor site and leads to the in-frame loss of 7 amino acids (represented as p.A302_K308del), including two G-X-Y canonical repeats within the triple helical region (Chen et al., 1996); Variants in this region are expected to disrupt normal protein folding and function, and this is an established mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25604898, 17347327, 25525159, 7977371, 8893763, 25592122, 32333414, 26037341, 35052477)

#	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 Invitae, SCV002240369.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 302 of the COL2A1 protein (p.Ala302Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 7 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Kniest dysplasia (PMID: 17347327, 25604898, 26037341). This variant is also known as p.Ala102Val. ClinVar contains an entry for this variant (Variation ID: 449001). 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) performed at Invitae indicates that this missense variant is not expected to disrupt COL2A1 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 12 (PMID: 7977371, 8893763). This variant disrupts the triple helix domain of COL2A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL2A1, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). 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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