VCV000008372.14 - ClinVar

NM_001001557.4(GDF6):c.866T>C (p.Leu289Pro)

Germline

Classification

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

Conflicting classifications of pathogenicity
Uncertain significance(2); Likely benign(1)

3 out of 5 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_001001557.4(GDF6):c.866T>C (p.Leu289Pro)

Variation ID: 8372 Accession: VCV000008372.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q22.1 8: 96145065 (GRCh38) [ NCBI UCSC ] 8: 97157293 (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	Oct 11, 2015	Feb 23, 2026	Dec 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001001557.4:c.866T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001001557.1:p.Leu289Pro	missense
NM_001001557.3:c.866T>C
NC_000008.11:g.96145065A>G
NC_000008.10:g.97157293A>G
NG_008981.1:g.20728T>C
	Q6KF10:p.Leu289Pro

... more HGVS ... less HGVS

Protein change

L289P

Other names

Canonical SPDI

NC_000008.11:96145064:A:G

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.

0.00020 (G)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00082

The Genome Aggregation Database (gnomAD) 0.00083

The Genome Aggregation Database (gnomAD) 0.00090

The Genome Aggregation Database (gnomAD), exomes 0.00006

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00034

Links

ClinGen: CA119556 UniProtKB: Q6KF10#VAR_046904 OMIM: 601147.0002 dbSNP: rs63751220 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.
GDF6		-	-	GRCh38 GRCh37	505	546

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.
Klippel-Feil syndrome 1, autosomal dominant	Pathogenic (1)	no assertion criteria provided	Aug 1, 2008	RCV000008878.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 6, 2016	RCV000255695.1
Isolated microphthalmia 4 Klippel-Feil syndrome 1, autosomal dominant Leber congenital amaurosis 17 Microphthalmia, isolated, with coloboma 6	Likely benign (1)	criteria provided, single submitter	Dec 29, 2025	RCV001399723.9
GDF6-related disorder	Likely benign (1)	no assertion criteria provided	Feb 8, 2024	RCV003952350.2
Isolated microphthalmia 4 Klippel-Feil syndrome 1, autosomal dominant Leber congenital amaurosis 17 Microphthalmia, isolated, with coloboma 6 Multiple synostoses syndrome 4	Uncertain significance (1)	criteria provided, single submitter	Jul 30, 2021	RCV005400410.1

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.
Uncertain significance (Jul 30, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Klippel-Feil syndrome 1, autosomal dominant Isolated microphthalmia 4 Microphthalmia, isolated, with coloboma 6 Leber congenital amaurosis 17 Multiple synostoses syndrome 4 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV006059243.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Uncertain significance (Jun 06, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000321718.6 First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016	Comment: show The L289P variant in the GDF6 gene has been reported previously in two unrelated patients with Klippel-Feil syndrome: an adult male with short neck, mirror movements, and left Sprengel anomaly, and a fetus with multiple segmentation abnormalities affecting the entire spine and ribs (Tassabehji et al., 2008). Both cases were said to be sporadic, but there is no evidence that family studies were performed. The L289P variant was not observed at any significant frequency in approximately 4500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L289P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variants in a nearby residue, E292D, has been reported in the Human Gene Mutation Database in association with Leber congenital amaurosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret L289P as a variant of uncertain significance. (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 (Dec 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Isolated microphthalmia 4 Leber congenital amaurosis 17 Klippel-Feil syndrome 1, autosomal dominant Microphthalmia, isolated, with coloboma 6 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001601520.6 First in ClinVar: May 16, 2021 Last updated: Feb 23, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 01, 2008) N Not contributing to aggregate classification	no assertion criteria provided	KLIPPEL-FEIL SYNDROME 1, AUTOSOMAL DOMINANT	OMIM Accession: SCV000029088.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 18425797 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In 2 unrelated patients with sporadic Klippel-Feil syndrome (KFS1; 118100), Tassabehji et al. (2008) identified a heterozygous 866T-C transition in exon 2 of the GDF6 … (more) In 2 unrelated patients with sporadic Klippel-Feil syndrome (KFS1; 118100), Tassabehji et al. (2008) identified a heterozygous 866T-C transition in exon 2 of the GDF6 gene, resulting in a leu289-to-pro (L289P) substitution in a conserved residue in the prodomain. The mutation was not found in 708 control chromosomes. One patient was an adult male with short neck, mirror movements, and left Sprengel anomaly. The second patient was a fetus assessed following termination of pregnancy for antenatal diagnosis of multiple segmentation abnormalities affecting the entire spine and ribs, as well as multiple other congenital anomalies. (less)

Likely benign (Feb 08, 2024) N Not contributing to aggregate classification	no assertion criteria provided	GDF6-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004780690.2 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:

The L289P variant in the GDF6 gene has been reported previously in two unrelated patients with Klippel-Feil syndrome: an adult male with short neck, mirror movements, and left Sprengel anomaly, and a fetus with multiple segmentation abnormalities affecting the entire spine and ribs (Tassabehji et al., 2008). Both cases were said to be sporadic, but there is no evidence that family studies were performed. The L289P variant was not observed at any significant frequency in approximately 4500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L289P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variants in a nearby residue, E292D, has been reported in the Human Gene Mutation Database in association with Leber congenital amaurosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret L289P as a variant of uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.	Tassabehji M	Human mutation	2008	PMID: 18425797

Text-mined citations for rs63751220 ...

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 Mar 01, 2026