VCV000357811.25 - ClinVar

NM_001851.6(COL9A1):c.902C>T (p.Pro301Leu)

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.

(8)

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(6); 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_001851.6(COL9A1):c.902C>T (p.Pro301Leu)

Variation ID: 357811 Accession: VCV000357811.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q13 6: 70281014 (GRCh38) [ NCBI UCSC ] 6: 70990717 (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 6, 2016	Nov 10, 2024	Oct 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001851.6:c.902C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001842.3:p.Pro301Leu	missense
NM_001377289.1:c.173C>T	NP_001364218.1:p.Pro58Leu	missense
NM_001377290.1:c.173C>T	NP_001364219.1:p.Pro58Leu	missense
NM_001377291.1:c.902C>T	NP_001364220.1:p.Pro301Leu	missense
NM_078485.4:c.173C>T	NP_511040.2:p.Pro58Leu	missense
NR_165185.1:n.318C>T		non-coding transcript variant
NC_000006.12:g.70281014G>A
NC_000006.11:g.70990717G>A
NG_011654.1:g.27070C>T

... more HGVS ... less HGVS

Protein change

P301L, P58L

Other names

Canonical SPDI

NC_000006.12:70281013: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) 0.00088

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

Exome Aggregation Consortium (ExAC) 0.00069

The Genome Aggregation Database (gnomAD), exomes 0.00074

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00079

The Genome Aggregation Database (gnomAD) 0.00083

Links

ClinGen: CA3882594 dbSNP: rs192047082 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.
COL9A1		No evidence available	No evidence available	GRCh38 GRCh37	1219	1267

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	Oct 28, 2024	RCV000991647.17
Hearing impairment	Uncertain significance (1)	criteria provided, single submitter	Apr 12, 2021	RCV001375076.3
Connective tissue disorder	Uncertain significance (1)	criteria provided, single submitter	Apr 1, 2020	RCV002278615.3
Stickler syndrome, type 4	Uncertain significance (1)	criteria provided, single submitter	Mar 1, 2023	RCV003447524.2
COL9A1-related disorder	Likely benign (1)	no assertion criteria provided	Mar 18, 2022	RCV003950271.2
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 14, 2024	RCV004767244.1

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 31, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001143285.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (1) PubMed: 24036952
Uncertain significance (Apr 12, 2021)	criteria provided, single submitter (ClinGen HL ACMG Specifications v1) Method: clinical testing	Hearing impairment Affected status: yes Allele origin: germline	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center Accession: SCV001571893.2 First in ClinVar: Apr 29, 2021 Last updated: Apr 29, 2021	Comment: PP3_Supporting Testing laboratory: CeGaT Praxis fuer Humangenetik Tuebingen
Uncertain significance (Apr 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002566398.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Uncertain significance (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Stickler syndrome, type 4 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004175853.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: The missense c.902C>T(p.Pro301Leu) variant in COL9A1 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Pro301Leu … (more) The missense c.902C>T(p.Pro301Leu) variant in COL9A1 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Pro301Leu variant has been reported with allele frequency of 0.07% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance (multiple submissions). The amino acid change p.Pro301Leu in COL9A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 301 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). (less)
Likely benign (Jan 29, 2024)	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: SCV001197802.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024
Uncertain significance (Aug 14, 2024)	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: SCV005381132.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: Variant summary: COL9A1 c.902C>T (p.Pro301Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: COL9A1 c.902C>T (p.Pro301Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 246936 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COL9A1 causing COL9A1-Related Disorders, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.902C>T in individuals affected with COL9A1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 357811). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Oct 28, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001763966.5 First in ClinVar: Aug 07, 2021 Last updated: Nov 10, 2024	Comment: Previously reported in a female with infantile malignant osteopetrosis who also harbored a homozygous frameshift variant in the TCIRG1 gene (Zhang (2016) http:/www.jcp-sh.org.cn/EN/Y2016/V34/I1/43 ); In … (more) Previously reported in a female with infantile malignant osteopetrosis who also harbored a homozygous frameshift variant in the TCIRG1 gene (Zhang (2016) http:/www.jcp-sh.org.cn/EN/Y2016/V34/I1/43 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function (less)
Likely benign (Mar 18, 2022)	no assertion criteria provided Method: clinical testing	COL9A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004766610.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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).

Comment:

The missense c.902C>T(p.Pro301Leu) variant in COL9A1 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Pro301Leu variant has been reported with allele frequency of 0.07% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance (multiple submissions). The amino acid change p.Pro301Leu in COL9A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 301 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

Comment:

Variant summary: COL9A1 c.902C>T (p.Pro301Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 246936 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COL9A1 causing COL9A1-Related Disorders, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.902C>T in individuals affected with COL9A1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 357811). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

Previously reported in a female with infantile malignant osteopetrosis who also harbored a homozygous frameshift variant in the TCIRG1 gene (Zhang (2016) http:/www.jcp-sh.org.cn/EN/Y2016/V34/I1/43 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function

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
Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.	Seddon JM	Nature genetics	2013	PMID: 24036952

Text-mined citations for rs192047082 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001851.6(COL9A1):c.902C>T (p.Pro301Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs192047082 ...