ClinVar Miner

Submissions for variant NM_152393.4(KLHL40):c.1498C>T (p.Arg500Cys)

gnomAD frequency: 0.00001  dbSNP: rs758188096
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487141 SCV000573504 likely pathogenic not provided 2023-05-28 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with studies showing absent KLHL40 expression in muscle (Seferian et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31060721, 27528495, 36233295, 37025449)
Labcorp Genetics (formerly Invitae), Labcorp RCV000525790 SCV000654243 pathogenic Nemaline myopathy 8 2022-08-31 criteria provided, single submitter clinical testing This variant is present in population databases (rs758188096, gnomAD 0.007%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters KLHL40 gene expression (PMID: 27528495). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KLHL40 protein function. ClinVar contains an entry for this variant (Variation ID: 423767). This missense change has been observed in individuals with autosomal recessive nemaline myopathy and congenital myopathy (PMID: 27528495; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 500 of the KLHL40 protein (p.Arg500Cys).
MGZ Medical Genetics Center RCV000525790 SCV002579986 likely pathogenic Nemaline myopathy 8 2022-05-23 criteria provided, single submitter clinical testing

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