VCV000547939.27 - ClinVar

NM_001852.4(COL9A2):c.458C>T (p.Pro153Leu)

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.

(6)

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(5); 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_001852.4(COL9A2):c.458C>T (p.Pro153Leu)

Variation ID: 547939 Accession: VCV000547939.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 40311675 (GRCh38) [ NCBI UCSC ] 1: 40777347 (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	Jul 9, 2018	Oct 20, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001852.4:c.458C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001843.1:p.Pro153Leu	missense
NC_000001.11:g.40311675G>A
NC_000001.10:g.40777347G>A
NG_008031.1:g.10593C>T

Protein change

P153L

Other names

Canonical SPDI

NC_000001.11:40311674: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.

0.00080 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00006

Exome Aggregation Consortium (ExAC) 0.00009

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Trans-Omics for Precision Medicine (TOPMed) 0.00031

The Genome Aggregation Database (gnomAD) 0.00051

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00080

Links

dbSNP: rs77937237 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.
COL9A2		No evidence available	No evidence available	GRCh38 GRCh37	997	1054

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.
Epiphyseal dysplasia, multiple, 2 Stickler syndrome, type 5	Uncertain significance (1)	criteria provided, single submitter	Mar 10, 2017	RCV000660517.5
not specified	Uncertain significance (1)	criteria provided, single submitter	May 11, 2020	RCV001199907.1
Epiphyseal dysplasia, multiple, 2	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001099057.4
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Apr 1, 2024	RCV001369753.20

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 (Mar 10, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Stickler syndrome, type 5 Epiphyseal dysplasia, multiple, 2 Affected status: unknown Allele origin: paternal	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000782618.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Epiphyseal dysplasia, multiple, 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001255466.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (May 11, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001370666.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020	Comment: Variant summary: COL9A2 c.458C>T (p.Pro153Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more) Variant summary: COL9A2 c.458C>T (p.Pro153Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250170 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in COL9A2 causing Epiphyseal dysplasia, multiple, 2 , allowing no conclusion about variant significance. To our knowledge, no occurrence of c.458C>T in individuals affected with Epiphyseal dysplasia, multiple, 2 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Aug 04, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001803550.4 First in ClinVar: Aug 21, 2021 Last updated: Aug 13, 2023	Comment: Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on … (more) Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function (less)
Likely benign (Dec 06, 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: SCV001566201.4 First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024
Uncertain significance (Apr 01, 2024)	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: SCV005041859.6 First in ClinVar: May 12, 2024 Last updated: Oct 20, 2024	Comment: COL9A2: PM2 Number of individuals with the variant: 1

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Variant summary: COL9A2 c.458C>T (p.Pro153Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250170 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in COL9A2 causing Epiphyseal dysplasia, multiple, 2 , allowing no conclusion about variant significance. To our knowledge, no occurrence of c.458C>T in individuals affected with Epiphyseal dysplasia, multiple, 2 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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 rs77937237 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001852.4(COL9A2):c.458C>T (p.Pro153Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs77937237 ...