VCV001879657.16 - ClinVar

NM_080680.3(COL11A2):c.4G>A (p.Glu2Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_080680.3(COL11A2):c.4G>A (p.Glu2Lys)

Variation ID: 1879657 Accession: VCV001879657.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.32 6: 33192237 (GRCh38) [ NCBI UCSC ] 6: 33160014 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 21, 2023	Oct 20, 2024	Dec 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_080680.3:c.4G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_542411.2:p.Glu2Lys	missense
NM_001163771.2:c.4G>A	NP_001157243.1:p.Glu2Lys	missense
NM_080679.3:c.4G>A	NP_542410.2:p.Glu2Lys	missense
NM_080681.3:c.4G>A	NP_542412.2:p.Glu2Lys	missense
NC_000006.12:g.33192237C>T
NC_000006.11:g.33160014C>T
NG_011589.1:g.5232G>A
NG_023374.1:g.13419G>A

... more HGVS ... less HGVS

Protein change

E2K

Other names

Canonical SPDI

NC_000006.12:33192236:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COL11A2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	2625	2636

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 13, 2023	RCV002512302.16
Otospondylomegaepiphyseal dysplasia, autosomal recessive	Uncertain significance (1)	criteria provided, single submitter	Aug 11, 2023	RCV003455532.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Otospondylomegaepiphyseal dysplasia, autosomal recessive Affected status: unknown Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004177172.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: The COL11A2 c.4G>A (p.Glu2Lys) variant, to our knowledge, has not been reported in the medical literature in an individual affected with a COL11A2-related disorder, but … (more) The COL11A2 c.4G>A (p.Glu2Lys) variant, to our knowledge, has not been reported in the medical literature in an individual affected with a COL11A2-related disorder, but has been reported in the ClinVar database as a germline variant of uncertain significance by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs immediately downstream of the ATG start site in the signal peptide, critical for proper protein localization (Lui VC et al., PMID: 8838804). Computational predictors suggest that the variant does not impact COL11A2 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. (less)
Uncertain significance (Dec 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004325991.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2 of the COL11A2 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2 of the COL11A2 protein (p.Glu2Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL11A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1879657). 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 COL11A2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Nov 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002821368.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: COL11A2: PM2 Number of individuals with the variant: 1

Comment:

The COL11A2 c.4G>A (p.Glu2Lys) variant, to our knowledge, has not been reported in the medical literature in an individual affected with a COL11A2-related disorder, but has been reported in the ClinVar database as a germline variant of uncertain significance by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs immediately downstream of the ATG start site in the signal peptide, critical for proper protein localization (Lui VC et al., PMID: 8838804). Computational predictors suggest that the variant does not impact COL11A2 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2 of the COL11A2 protein (p.Glu2Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL11A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1879657). 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 COL11A2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_080680.3(COL11A2):c.4G>A (p.Glu2Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...