VCV002630909.2 - ClinVar

NM_001854.4(COL11A1):c.5357dup (p.Asn1786fs)

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.

(2)

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_001854.4(COL11A1):c.5357dup (p.Asn1786fs)

Variation ID: 2630909 Accession: VCV002630909.2

Type and length

Duplication, 1 bp

Location

Cytogenetic: 1p21.1 1: 102878082-102878083 (GRCh38) [ NCBI UCSC ] 1: 103343638-103343639 (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	Nov 20, 2023	Feb 20, 2024	Sep 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001854.4:c.5357dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001845.3:p.Asn1786fs	frameshift
NM_001168249.1:c.5008dup	NP_001161721.1:p.Asn1670Lysfs	frameshift
NM_001190709.2:c.5240dup	NP_001177638.1:p.Asn1747fs	frameshift
NM_080629.3:c.5393dup	NP_542196.2:p.Asn1798fs	frameshift
NM_080630.4:c.5009dup	NP_542197.3:p.Asn1670fs	frameshift
NR_134980.2:n.5717dup		non-coding transcript variant
NC_000001.11:g.102878084dup
NC_000001.10:g.103343640dup
NG_008033.2:g.235414dup

... more HGVS ... less HGVS

Protein change

N1670fs, N1747fs, N1786fs, N1798fs

Other names

Canonical SPDI

NC_000001.11:102878082:TT:TTT

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.
COL11A1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2674	2771

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 (1)	criteria provided, single submitter	Mar 1, 2023	RCV003720893.2
COL11A1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Sep 14, 2023	RCV004527948.1

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 (Sep 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	COL11A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004103643.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The COL11A1 c.5357dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn1786Lysfs2). This variant occurs in the last exon, and no … (more) The COL11A1 c.5357dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn1786Lysfs2). This variant occurs in the last exon, and no premature termination variants downstream of this position have been reported as pathogenic. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Mar 01, 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: SCV004503782.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 23922384 Comment: This sequence change creates a premature translational stop signal (p.Asn1786Lysfs2) in the COL11A1 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Asn1786Lysfs2) in the COL11A1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the COL11A1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL11A1-related conditions. This variant disrupts a region of the COL11A1 protein in which other variant(s) (p.Gly1800Cys) have been observed in individuals with COL11A1-related conditions (PMID: 23922384). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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)

Comment:

The COL11A1 c.5357dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn1786Lysfs*2). This variant occurs in the last exon, and no premature termination variants downstream of this position have been reported as pathogenic. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

This sequence change creates a premature translational stop signal (p.Asn1786Lysfs*2) in the COL11A1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the COL11A1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL11A1-related conditions. This variant disrupts a region of the COL11A1 protein in which other variant(s) (p.Gly1800Cys) have been observed in individuals with COL11A1-related conditions (PMID: 23922384). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

Title	Author	Journal	Year	Link
Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss.	Richards AJ	Journal of medical genetics	2013	PMID: 23922384

Text-mined citations for this variant ...

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_001854.4(COL11A1):c.5357dup (p.Asn1786fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...