ClinVar Miner

Submissions for variant NM_001001557.4(GDF6):c.169G>C (p.Asp57His)

gnomAD frequency: 0.00006  dbSNP: rs397514725
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001337031 SCV001530589 likely pathogenic Klippel-Feil syndrome 1, autosomal dominant 2018-11-11 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID:23307924]
GeneDx RCV001753472 SCV001985468 uncertain significance not provided 2019-06-24 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect. D57H shown to significantly reduce transcription activation in exogenous reporter assay in COS7 cells (Asai-Coakwell et al., 2013).; This variant is associated with the following publications: (PMID: 23307924, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp RCV001853075 SCV002295520 uncertain significance Klippel-Feil syndrome 1, autosomal dominant; Isolated microphthalmia 4; Microphthalmia, isolated, with coloboma 6; Leber congenital amaurosis 17 2023-11-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 57 of the GDF6 protein (p.Asp57His). This variant is present in population databases (rs397514725, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of Leber congenital amaurosis (PMID: 23307924). ClinVar contains an entry for this variant (Variation ID: 60534). 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 tolerated. Experimental studies have shown that this missense change affects GDF6 function (PMID: 23307924). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics RCV000054426 SCV003841222 uncertain significance Leber congenital amaurosis 17 criteria provided, single submitter clinical testing
OMIM RCV000054426 SCV000082903 pathogenic Leber congenital amaurosis 17 2013-04-01 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004757958 SCV005347906 uncertain significance GDF6-related disorder 2024-04-03 no assertion criteria provided clinical testing The GDF6 c.169G>C variant is predicted to result in the amino acid substitution p.Asp57His. This variant was reported along with a second potentially causative variant in an individual with Leber congenital amaurosis (Asai-Coakwell et al. 2013. PubMed ID: 23307924). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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