ClinVar Miner

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

gnomAD frequency: 0.00090  dbSNP: rs63751220
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255695 SCV000321718 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing 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.
Invitae RCV001399723 SCV001601520 likely benign Klippel-Feil syndrome 1, autosomal dominant; Isolated microphthalmia 4; Microphthalmia, isolated, with coloboma 6; Leber congenital amaurosis 17 2024-01-22 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003952350 SCV004780690 likely benign GDF6-related disorder 2024-02-08 criteria provided, single submitter clinical testing 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).
OMIM RCV000008878 SCV000029088 pathogenic Klippel-Feil syndrome 1, autosomal dominant 2008-08-01 no assertion criteria provided literature only

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