VCV000198360.28 - ClinVar

NM_001854.4(COL11A1):c.5198G>A (p.Arg1733His)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

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

9 out of 12 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001854.4(COL11A1):c.5198G>A (p.Arg1733His)

Variation ID: 198360 Accession: VCV000198360.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.1 1: 102879759 (GRCh38) [ NCBI UCSC ] 1: 103345315 (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	Jun 29, 2015	Dec 14, 2025	Nov 10, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001854.4:c.5198G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001845.3:p.Arg1733His	missense
NM_001190709.2:c.5081G>A	NP_001177638.1:p.Arg1694His	missense
NM_080629.3:c.5234G>A	NP_542196.2:p.Arg1745His	missense
NM_080630.4:c.4850G>A	NP_542197.3:p.Arg1617His	missense
NR_134980.2:n.5558G>A		non-coding transcript variant
NC_000001.11:g.102879759C>T
NC_000001.10:g.103345315C>T
NG_008033.2:g.233738G>A

... more HGVS ... less HGVS

Protein change

R1745H, R1733H, R1694H, R1617H

Other names

Canonical SPDI

NC_000001.11:102879758:C:T

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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

The Genome Aggregation Database (gnomAD) 0.00040

The Genome Aggregation Database (gnomAD), exomes 0.00042

Exome Aggregation Consortium (ExAC) 0.00044

The Genome Aggregation Database (gnomAD) 0.00044

The Genome Aggregation Database (gnomAD), exomes 0.00045

Trans-Omics for Precision Medicine (TOPMed) 0.00048

Links

ClinGen: CA246966 dbSNP: rs140250347 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	3107	3225
LOC126805814	-	-	-	GRCh38	-	88

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 classifications of pathogenicity (6)	criteria provided, conflicting classifications	Jan 23, 2025	RCV000179660.24
Stickler syndrome type 2	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000271060.5
Fibrochondrogenesis 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000357636.5
Connective tissue disorder	Likely benign (1)	criteria provided, single submitter	Jun 1, 2018	RCV000680455.1
Marshall syndrome	Likely benign (1)	criteria provided, single submitter	Jan 1, 2019	RCV001262338.1
COL11A1-related disorder	Likely benign (1)	no assertion criteria provided	Jul 6, 2023	RCV004539684.2
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 10, 2025	RCV006268653.1

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.	Expand all rows Collapse all rows 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.
Likely benign (Jun 01, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Connective tissue disorder	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000807828.1 First in ClinVar: Sep 22, 2018 Last updated: Sep 22, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Jun 27, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria)	not provided	Athena Diagnostics Accession: SCV001143580.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Stickler syndrome type 2	Illumina Laboratory Services, Illumina Accession: SCV000346327.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Fibrochondrogenesis 1	Illumina Laboratory Services, Illumina Accession: SCV000346329.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jan 01, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Marshall syndrome	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440162.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Likely benign (Apr 12, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV001780620.2 First in ClinVar: Aug 13, 2021 Last updated: Apr 23, 2023	Comment: show See Variant Classification Assertion Criteria. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (Jan 23, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001068940.7 First in ClinVar: Dec 17, 2019 Last updated: Feb 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Nov 16, 2016) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000231943.6 First in ClinVar: Jun 29, 2015 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL11A1 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed

Uncertain significance (Nov 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV007124241.1 First in ClinVar: Dec 14, 2025 Last updated: Dec 14, 2025	Comment: show Variant summary: COL11A1 c.5198G>A (p.Arg1733His) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00045 in 251036 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in COL11A1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5198G>A in individuals affected with COL11A1-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 198360). Based on the evidence outlined above, the variant was classified as uncertain significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979877.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980101.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (Jul 06, 2023) N Not contributing to aggregate classification	no assertion criteria provided	COL11A1-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004762741.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Variant summary: COL11A1 c.5198G>A (p.Arg1733His) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00045 in 251036 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in COL11A1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5198G>A in individuals affected with COL11A1-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 198360). Based on the evidence outlined above, the variant was classified as uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL11A1	-	-	-	-

Text-mined citations for rs140250347 ...

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 Dec 20, 2025

ClinVar Genomic variation as it relates to human health

NM_001854.4(COL11A1):c.5198G>A (p.Arg1733His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs140250347 ...