ClinVar Miner

Submissions for variant NM_152393.4(KLHL40):c.1582G>A (p.Glu528Lys)

gnomAD frequency: 0.00001  dbSNP: rs397509419
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268125 SCV001446793 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
3billion RCV000054410 SCV002011918 likely pathogenic Nemaline myopathy 8 2021-10-02 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic supporitng evidence (ClinVar ID: VCV000060512.2, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000637, PM2). The variant was observed in trans with a pathogenic variant (NM_152393.3:c.1281_1294del) as compound heterozygous (3billion dataset, PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.875, PP3). Patient's phenotype is considered compatible with Nemaline myopathy 8, autosomal recessive (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV000054410 SCV002245955 pathogenic Nemaline myopathy 8 2022-05-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 528 of the KLHL40 protein (p.Glu528Lys). This variant is present in population databases (rs397509419, gnomAD 0.09%). This missense change has been observed in individuals with nemaline myopathy (PMID: 23746549). ClinVar contains an entry for this variant (Variation ID: 60512). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this missense change alters KLHL40 gene expression (PMID: 24960163).
OMIM RCV000054410 SCV000082887 pathogenic Nemaline myopathy 8 2013-07-11 no assertion criteria provided literature only

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