VCV000735068.15 - ClinVar

NM_001854.4(COL11A1):c.560C>T (p.Thr187Met)

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.

(5)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001854.4(COL11A1):c.560C>T (p.Thr187Met)

Variation ID: 735068 Accession: VCV000735068.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.1 1: 103074709 (GRCh38) [ NCBI UCSC ] 1: 103540265 (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	Dec 17, 2019	Sep 29, 2024	May 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001854.4:c.560C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001845.3:p.Thr187Met	missense
NM_001190709.2:c.560C>T	NP_001177638.1:p.Thr187Met	missense
NM_080629.3:c.560C>T	NP_542196.2:p.Thr187Met	missense
NM_080630.4:c.560C>T	NP_542197.3:p.Thr187Met	missense
NR_134980.2:n.904C>T		non-coding transcript variant
NC_000001.11:g.103074709G>A
NC_000001.10:g.103540265G>A
NG_008033.2:g.38788C>T

... more HGVS ... less HGVS

Protein change

T187M

Other names

Canonical SPDI

NC_000001.11:103074708:G:A

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.

0.00060 (A)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00028

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

Links

dbSNP: rs184606223 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	2694	2791

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	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	May 6, 2024	RCV000910558.15
Fibrochondrogenesis 1	Uncertain significance (1)	criteria provided, single submitter	May 28, 2019	RCV000986392.1
COL11A1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Aug 3, 2023	RCV004533488.1

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 (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Fibrochondrogenesis 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135387.1 First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020
Uncertain significance (Aug 03, 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: SCV004120684.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The COL11A1 c.560C>T variant is predicted to result in the amino acid substitution p.Thr187Met. This variant was reported in an individual with early onset hearing … (more) The COL11A1 c.560C>T variant is predicted to result in the amino acid substitution p.Thr187Met. This variant was reported in an individual with early onset hearing loss (Table S2, Miyagawa. 2013. PubMed ID: 23967202) and in the compound heterozygous state along with another potentially disease causing variant in a patient with multiple congenital anomalies (Table S2, Wang. 2021. PubMed ID: 33502061). This variant is reported in 0.38% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-103540265-G-A), which is likely too high to be a fully penetrant disease causing variant for autosomal dominant disease in this gene. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Apr 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003831156.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely benign (Dec 10, 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: SCV001055428.4 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024
Uncertain significance (May 06, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001789983.3 First in ClinVar: Aug 21, 2021 Last updated: Sep 29, 2024	Comment: Reported in association with early-onset sensorineural hearing loss in published literature (PMID: 23967202, 23767834); however, detailed clinical information not provided; Identified in an individual with … (more) Reported in association with early-onset sensorineural hearing loss in published literature (PMID: 23967202, 23767834); however, detailed clinical information not provided; Identified in an individual with a second COL11A1 variant on the opposite allele (in trans) from a cohort of newborns with multiple congenital anomalies (PMID: 33502061); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD; PMID: 25240749); This variant is associated with the following publications: (PMID: 34426522, 32112773, 23967202, 23767834, 33502061, 25240749) (less)

Comment:

The COL11A1 c.560C>T variant is predicted to result in the amino acid substitution p.Thr187Met. This variant was reported in an individual with early onset hearing loss (Table S2, Miyagawa. 2013. PubMed ID: 23967202) and in the compound heterozygous state along with another potentially disease causing variant in a patient with multiple congenital anomalies (Table S2, Wang. 2021. PubMed ID: 33502061). This variant is reported in 0.38% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-103540265-G-A), which is likely too high to be a fully penetrant disease causing variant for autosomal dominant disease in this gene. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

Reported in association with early-onset sensorineural hearing loss in published literature (PMID: 23967202, 23767834); however, detailed clinical information not provided; Identified in an individual with a second COL11A1 variant on the opposite allele (in trans) from a cohort of newborns with multiple congenital anomalies (PMID: 33502061); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD; PMID: 25240749); This variant is associated with the following publications: (PMID: 34426522, 32112773, 23967202, 23767834, 33502061, 25240749)

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 rs184606223 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001854.4(COL11A1):c.560C>T (p.Thr187Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs184606223 ...