ClinVar Miner

Submissions for variant NM_172362.3(KCNH1):c.1486G>A (p.Gly496Arg) (rs730882175)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498687 SCV000589774 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The G496R variant in the KCNH1 gene has been reported previously, using alternate nomenclature G469R, on exome sequencing as a de novo finding in an individual with features of Zimmermann-Laband syndrome (Kortum et al., 2015). The G496R variant is not observed in large population cohorts (Lek et al., 2016). The G496R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, functional studies demonstrate that the G496R variant results in a gain of function effect (Kortum et al., 2015). A missense variant at this same residue (G496E) has been previously reported on exome sequencing as a de novo finding in an individual with features of Zimmermann-Laband syndrome (Fukai et al., 2016), supporting the functional importance of this residue of the protein. We interpret G496R as a pathogenic variant.
Institute of Human Genetics,Klinikum rechts der Isar RCV000190321 SCV000680267 pathogenic Zimmermann-Laband syndrome 1 2017-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623955 SCV000741941 likely pathogenic Inborn genetic diseases 2016-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità RCV000190321 SCV000212229 pathogenic Zimmermann-Laband syndrome 1 no assertion criteria provided not provided Converted during submission to Pathogenic.
OMIM RCV000190321 SCV000238500 pathogenic Zimmermann-Laband syndrome 1 2015-06-01 no assertion criteria provided literature only

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