VCV000030591.34 - ClinVar

NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)

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
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)

Variation ID: 30591 Accession: VCV000030591.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.31 12: 7690177 (GRCh38) [ NCBI UCSC ] 12: 7842773 (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	Oct 20, 2024	Jan 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020634.3:c.796C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065685.1:p.Arg266Cys	missense
NC_000012.12:g.7690177G>A
NC_000012.11:g.7842773G>A
NG_028167.1:g.10588C>T
	Q9NR23:p.Arg266Cys

... more HGVS ... less HGVS

Protein change

R266C

Other names

Canonical SPDI

NC_000012.12:7690176: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.

0.00040 (A)

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

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

Trans-Omics for Precision Medicine (TOPMed) 0.00127

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00169

The Genome Aggregation Database (gnomAD) 0.00188

Links

ClinGen: CA129363 UniProtKB: Q9NR23#VAR_065148 OMIM: 606522.0001 dbSNP: rs140926412 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.
GDF3		-	-	GRCh38 GRCh37	59	108

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.
Microphthalmia, isolated, with coloboma 6	Pathogenic (1)	no assertion criteria provided	Jan 15, 2010	RCV000023556.6
Klippel-Feil syndrome 3, autosomal dominant	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 18, 2024	RCV000023555.8
Hemivertebrae Missing ribs Scoliosis Supernumerary ribs	Likely benign (1)	criteria provided, single submitter	Feb 10, 2014	RCV000414875.3
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 9, 2024	RCV001091141.23
GDF3-related disorder	Benign (1)	no assertion criteria provided	Nov 13, 2019	RCV003924856.2

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 benign (Jan 18, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Klippel-Feil syndrome 3, autosomal dominant Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002998092.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024
Likely benign (Feb 10, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemivertebrae Missing ribs Scoliosis Supernumerary ribs Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492804.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Uncertain significance (Jan 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325153.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Observed in patients with features of GDF3-related ocular and skeletal anomalies spectrum disorder (PMID: 19864492); Published functional studies demonstrate a damaging effect on protein maturation … (more) Observed in patients with features of GDF3-related ocular and skeletal anomalies spectrum disorder (PMID: 19864492); Published functional studies demonstrate a damaging effect on protein maturation (PMID: 29735971); This variant is associated with the following publications: (PMID: 29260090, 30653986, 34426522, 35170016, 30665703, 24278672, 33195419, 19864492, 23307924, 28440294, 30940639, 25348728, 29735971) (less)
Likely pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Klippel-Feil syndrome 3, autosomal dominant Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001441021.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Pathogenic (Jul 01, 2017)	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: SCV001247012.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Jan 15, 2010)	no assertion criteria provided Method: literature only	KLIPPEL-FEIL SYNDROME 3, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044846.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 19864492 Comment on evidence: In a 3-generation North American family with Klippel-Feil syndrome (KFS3; 613702) as well as unilateral iris and retinal coloboma in the proband, Ye et al. … (more) In a 3-generation North American family with Klippel-Feil syndrome (KFS3; 613702) as well as unilateral iris and retinal coloboma in the proband, Ye et al. (2010) identified a heterozygous 796C-T transition in the GDF3 gene, resulting in an arg266-to-cys (R266C) substitution at a highly conserved residue, which increases the number of cysteine residues in the mature TGF-beta domain. The R266C mutation was not found in 480 control DNA samples. Western blot analysis of transfected COS-7 cell lysates detected reduced amounts of mature R266C-mutant protein in the cytosol with striking reduction in the amount of mature R266C protein in medium. The authors also reported a European male, born of consanguineous parents, with isolated microphthalmia and bilateral coloboma (MCOPCB6; 613703) who was heterozygous for the R266C mutation. The individual's only bony defect was an anomalous right temporal bone. Ye et al. (2010) also described a European mother and daughter with MCOPCB6. The mother showed heterozygosity for the R266C mutation, and her daughter showed double heterozygosity for the R266C mutation and an A199T mutation (601147.0007) in the GDF6 gene. The daughter exhibited a more severe phenotype with nystagmus, bilateral iris coloboma, severe colobomatous microphthalmia, and bilateral foveal hypoplasia. Visual acuity was 20/200. MRI showed abnormally small optic discs with reduced optic nerve diameter, and ERG showed reduced a- and b-wave amplitude. (less)
Pathogenic (Jan 15, 2010)	no assertion criteria provided Method: literature only	MICROPHTHALMIA/COLOBOMA 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV004697471.2 First in ClinVar: Mar 05, 2024 Last updated: Mar 10, 2024	Publications: PubMed (1) PubMed: 19864492 Comment on evidence: In a 3-generation North American family with Klippel-Feil syndrome (KFS3; 613702) as well as unilateral iris and retinal coloboma in the proband, Ye et al. … (more) In a 3-generation North American family with Klippel-Feil syndrome (KFS3; 613702) as well as unilateral iris and retinal coloboma in the proband, Ye et al. (2010) identified a heterozygous 796C-T transition in the GDF3 gene, resulting in an arg266-to-cys (R266C) substitution at a highly conserved residue, which increases the number of cysteine residues in the mature TGF-beta domain. The R266C mutation was not found in 480 control DNA samples. Western blot analysis of transfected COS-7 cell lysates detected reduced amounts of mature R266C-mutant protein in the cytosol with striking reduction in the amount of mature R266C protein in medium. The authors also reported a European male, born of consanguineous parents, with isolated microphthalmia and bilateral coloboma (MCOPCB6; 613703) who was heterozygous for the R266C mutation. The individual's only bony defect was an anomalous right temporal bone. Ye et al. (2010) also described a European mother and daughter with MCOPCB6. The mother showed heterozygosity for the R266C mutation, and her daughter showed double heterozygosity for the R266C mutation and an A199T mutation (601147.0007) in the GDF6 gene. The daughter exhibited a more severe phenotype with nystagmus, bilateral iris coloboma, severe colobomatous microphthalmia, and bilateral foveal hypoplasia. Visual acuity was 20/200. MRI showed abnormally small optic discs with reduced optic nerve diameter, and ERG showed reduced a- and b-wave amplitude. (less)
Benign (Nov 13, 2019)	no assertion criteria provided Method: clinical testing	GDF3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004747301.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

Observed in patients with features of GDF3-related ocular and skeletal anomalies spectrum disorder (PMID: 19864492); Published functional studies demonstrate a damaging effect on protein maturation (PMID: 29735971); This variant is associated with the following publications: (PMID: 29260090, 30653986, 34426522, 35170016, 30665703, 24278672, 33195419, 19864492, 23307924, 28440294, 30940639, 25348728, 29735971)

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
Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.	Ye M	Human molecular genetics	2010	PMID: 19864492

Text-mined citations for rs140926412 ...

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_020634.3(GDF3):c.796C>T (p.Arg266Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140926412 ...