VCV000002126.16 - ClinVar

NM_001278431.2(C1QTNF5):c.489C>G (p.Ser163Arg)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

6 out of 8 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_001278431.2(C1QTNF5):c.489C>G (p.Ser163Arg)

Variation ID: 2126 Accession: VCV000002126.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 119339574 (GRCh38) [ NCBI UCSC ] 11: 119210284 (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	Apr 4, 2013	Apr 13, 2025	Jul 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001278431.2:c.489C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001265360.1:p.Ser163Arg	missense
NM_031433.4:c.*1385C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_015645.5:c.489C>G	NP_056460.1:p.Ser163Arg	missense
NC_000011.10:g.119339574G>C
NC_000011.9:g.119210284G>C
NG_012235.1:g.12100C>G
	Q9BXJ0:p.Ser163Arg

... more HGVS ... less HGVS

Protein change

S163R

Other names

C1QTNF5, SER163ARG

Canonical SPDI

NC_000011.10:119339573:G:C

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

ClinGen: CA017306 UniProtKB: Q9BXJ0#VAR_032629 OMIM: 608752.0001 dbSNP: rs111033578 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.
MFRP		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	5	908
C1QTNF5		-	-	GRCh38 GRCh37	1	904

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.
Late-onset retinal degeneration	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 17, 2023	RCV000002208.8
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2019	RCV001074679.4
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 8, 2024	RCV001245416.15

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.
Likely pathogenic (Jun 12, 2012) C Contributing to aggregate classification	criteria provided, single submitter (Lee et al. (JAMA. 2014)) Method: clinical testing	Late-onset retinal degeneration (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	UCLA Clinical Genomics Center, UCLA Study: CES Accession: SCV000255333.3 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2025	Age: 70-79 years Sex: female Ethnicity/Population group: European Caucasian (Norway) Testing laboratory: UCLA Clinical Genomics Center
Pathogenic (Mar 20, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240272.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jul 08, 2024) C Contributing to aggregate classification	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: SCV001418703.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 12944416‚ 23289492‚ 29847639‚ 24531000 Comment: This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 163 of the C1QTNF5 protein (p.Ser163Arg). … (more) This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 163 of the C1QTNF5 protein (p.Ser163Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with late-onset retinal degeneration (PMID: 12944416, 23289492, 29847639). It has also been observed to segregate with disease in related individuals. This variant is also known as c.686C>G. ClinVar contains an entry for this variant (Variation ID: 2126). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects C1QTNF5 function (PMID: 24531000). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 17, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762129.2 First in ClinVar: Jul 30, 2021 Last updated: Apr 13, 2025	Clinical Features: Retinal dystrophy (present) , Rod-cone dystrophy (present) Sex: male
Pathogenic (Jan 29, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001787252.1 First in ClinVar: Aug 18, 2021 Last updated: Aug 18, 2021	Comment: Most common pathogenic variant associated with late-onset retinal degeneration (Hayward et al., 2003; Stanton et al., 2017); Published functional studies demonstrate a damaging effect with … (more) Most common pathogenic variant associated with late-onset retinal degeneration (Hayward et al., 2003; Stanton et al., 2017); Published functional studies demonstrate a damaging effect with aggregate formation in vitro and pathological effects in mice that were similar to patients with late-onset retinal degeneration (Hayward et al., 2003; Dinculescu et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29721928, 31385385, 29555955, 12944416, 26513502, 26197217, 22110650, 24531000, 22892318, 21349921, 23289492) (less)
Pathogenic (Aug 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Late-onset retinal degeneration (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004032299.2 First in ClinVar: Sep 09, 2023 Last updated: Apr 13, 2025	Comment: Criteria applied: PS1,PS3,PS4_MOD,PM1_SUP,PM2_SUP,PP3 Clinical Features: Diabetes mellitus (present) , Night blindness (present) , Cone-rod dystrophy (present) , Hearing impairment (present) , Visual impairment (present) , Increased blood pressure (present) , Retinal dystrophy (present) , Macular dystrophy (present) Sex: female
Pathogenic (Oct 15, 2003) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	RETINAL DEGENERATION, LATE-ONSET, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022366.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 12944416 Comment on evidence: In affected members of 7 unrelated families with late-onset retinal degeneration (LORD; 605670), Hayward et al. (2003) described a C-to-G transversion at nucleotide 686 in … (more) In affected members of 7 unrelated families with late-onset retinal degeneration (LORD; 605670), Hayward et al. (2003) described a C-to-G transversion at nucleotide 686 in exon 3 of the CTRP5 gene that resulted in a ser163-to-arg (S163R) amino acid substitution. The affected members of these 7 Scottish and North American families shared a 3-Mb haplotype on chromosome 11q23, suggesting a founder effect. The highly evolutionarily conserved serine-163 lies in the carboxy-terminal C1q region, a region which is thought to be essential for trimerization of the collagen domain. Biochemical studies revealed a propensity for high molecular weight aggregates of the mutant protein. (less)
Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Late-onset retinal degeneration Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760265.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021

Comment:

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 163 of the C1QTNF5 protein (p.Ser163Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with late-onset retinal degeneration (PMID: 12944416, 23289492, 29847639). It has also been observed to segregate with disease in related individuals. This variant is also known as c.686C>G. ClinVar contains an entry for this variant (Variation ID: 2126). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects C1QTNF5 function (PMID: 24531000). For these reasons, this variant has been classified as Pathogenic.

Comment:

Most common pathogenic variant associated with late-onset retinal degeneration (Hayward et al., 2003; Stanton et al., 2017); Published functional studies demonstrate a damaging effect with aggregate formation in vitro and pathological effects in mice that were similar to patients with late-onset retinal degeneration (Hayward et al., 2003; Dinculescu et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29721928, 31385385, 29555955, 12944416, 26513502, 26197217, 22110650, 24531000, 22892318, 21349921, 23289492)

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
Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families.	Martin-Merida I	Investigative ophthalmology & visual science	2018	PMID: 29847639
The macular degeneration-linked C1QTNF5 (S163) mutation causes higher-order structural rearrangements.	Tu X	Journal of structural biology	2014	PMID: 24531000
Phenotypic findings in C1QTNF5 retinopathy (late-onset retinal degeneration).	Soumplis V	Acta ophthalmologica	2013	PMID: 23289492
Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration.	Hayward C	Human molecular genetics	2003	PMID: 12944416

Text-mined citations for rs111033578 ...

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 Apr 13, 2025

ClinVar Genomic variation as it relates to human health

NM_001278431.2(C1QTNF5):c.489C>G (p.Ser163Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111033578 ...