NM_001001557.4(GDF6):c.1271A>G (p.Lys424Arg) AND Klippel-Feil syndrome 1, autosomal dominant

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 30, 2014
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000008879.10

Allele description [Variation Report for NM_001001557.4(GDF6):c.1271A>G (p.Lys424Arg)]

NM_001001557.4(GDF6):c.1271A>G (p.Lys424Arg)

Gene:

GDF6:growth differentiation factor 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q22.1

Genomic location:

Preferred name:

NM_001001557.4(GDF6):c.1271A>G (p.Lys424Arg)

Other names:

K242R

HGVS:

NC_000008.11:g.96144660T>C
NG_008981.1:g.21133A>G
NM_001001557.4:c.1271A>GMANE SELECT
NP_001001557.1:p.Lys424Arg
NC_000008.10:g.97156888T>C
NM_001001557.2:c.1271A>G
NM_001001557.3:c.1271A>G
Q6KF10:p.Lys424Arg

Protein change:

K424R; LYS242ARG

Links:

UniProtKB: Q6KF10#VAR_063029; OMIM: 601147.0003; dbSNP: rs121909353

Molecular consequence:

NM_001001557.4:c.1271A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Klippel-Feil syndrome 1, autosomal dominant (KFS1)
Synonyms:: CERVICAL VERTEBRAL FUSION, AUTOSOMAL DOMINANT
Identifiers:: MONDO: MONDO:0007306; MedGen: C1861689; Orphanet: 2345; OMIM: 118100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000029089	OMIM	no assertion criteria provided	Pathogenic (Mar 15, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000328724	Baylor Genetics	no assertion criteria provided	Pathogenic (Dec 30, 2014)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000029089

OMIM

no assertion criteria provided

Pathogenic
(Mar 15, 2009)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000328724

Baylor Genetics

no assertion criteria provided

Pathogenic
(Dec 30, 2014)

paternal

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	paternal	unknown	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes.

Asai-Coakwell M, French CR, Ye M, Garcha K, Bigot K, Perera AG, Staehling-Hampton K, Mema SC, Chanda B, Mushegian A, Bamforth S, Doschak MR, Li G, Dobbs MB, Giampietro PF, Brooks BP, Vijayalakshmi P, Sauvé Y, Abitbol M, Sundaresan P, van Heyningen V, Pourquié O, et al.

Hum Mol Genet. 2009 Mar 15;18(6):1110-21. doi: 10.1093/hmg/ddp008. Epub 2009 Jan 6.

PubMed [citation]

PMID:: 19129173
PMCID:: PMC12118964

Details of each submission

From OMIM, SCV000029089.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with hemivertebrae and rib malformations, or Klippel-Feil syndrome (KFS1; 118100), Asai-Coakwell et al. (2009) identified heterozygosity for a 1271A-G transition in exon 2 of the GDF6 gene, predicted to result in a lys424-to-arg (K424R) substitution at a highly conserved residue in the propeptide domain. Functional studies showed significantly reduced reporter activity and reduced levels of mature ligand with mutant GDF6 compared to wildtype, indicating that K424R represents a hypomorphic mutation. The mutation was not found in 366 controls. The authors noted that in addition to skeletal anomalies, this patient also had fused (horseshoe) kidney.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV000328724.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (1)

Description

Our laboratory reported dual molecular diagnoses in GDF6 (NM_001001557.2, c.1271A>G) and SOX10 (NM_006941.3, c.316C>G) in one individual with reported features of developmental delay and unilateral hearing loss. The GDF6 variant has been previously reported as disease-causing (PMID 19129173). Additionally, this same variant was also seen in a 48-year-old male with migraines, white matter changes, intracerebral hemorrhages, episodes of hemiparesis and dysarthria, renal cysts, hematuria.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	unknown	not provided	not provided	not provided	(GTR000508680.4)	2	not provided	2	not provided

Last Updated: Mar 7, 2026

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