ClinVar Miner

Submissions for variant NM_152393.4(KLHL40):c.1405G>A (p.Gly469Ser)

gnomAD frequency: 0.00006  dbSNP: rs367579275
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000850392 SCV000992580 uncertain significance Nemaline myopathy 8 2019-07-01 criteria provided, single submitter research ACMG codes: PM2, PM5, PP3
Labcorp Genetics (formerly Invitae), Labcorp RCV000850392 SCV001236922 pathogenic Nemaline myopathy 8 2023-03-31 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly469 amino acid residue in KLHL40. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23746549, 25721947). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KLHL40 protein function. ClinVar contains an entry for this variant (Variation ID: 689641). This missense change has been observed in individual(s) with clinical features of nemaline myopathy (PMID: 34930662; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs367579275, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 469 of the KLHL40 protein (p.Gly469Ser).
MGZ Medical Genetics Center RCV000850392 SCV002579984 uncertain significance Nemaline myopathy 8 2022-05-23 criteria provided, single submitter clinical testing
GeneDx RCV004726701 SCV005332363 likely pathogenic not provided 2023-12-19 criteria provided, single submitter clinical testing 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: 34930662, 25721947, 23746549, 35131284, 36233295, 37025449)
Al Jawhara Center for Molecular Medicine, Arabian Gulf University RCV000850392 SCV003762116 likely pathogenic Nemaline myopathy 8 2023-01-20 no assertion criteria provided clinical testing severe myopathy, nemaline rods, infancy death

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