Submissions for variant NM_152393.4(KLHL40):c.1516A>C (p.Thr506Pro)

gnomAD frequency: 0.00002  dbSNP: rs778022582

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050162	SCV001214258	pathogenic	Nemaline myopathy 8	2022-11-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 846771). This missense change has been observed in individual(s) with nemaline myopathy and/or fetal akinesia deformation sequence (PMID: 23746549, 27762439, 31360996). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778022582, gnomAD 0.1%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 506 of the KLHL40 protein (p.Thr506Pro).
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong	RCV001050162	SCV001293796	pathogenic	Nemaline myopathy 8	2020-02-01	criteria provided, single submitter	research	We identified six cases of nemaline myopathy 8 which involves the c.1516A>C variant, from five unrelated families of non-consanguineous southern Chinese. All unrelated patients carried a homozygous c.1516A>C p.(Thr506Pro) mutation, except for two siblings who carried compound heterozygous variants of another variant. Common prenatal features included reduced fetal movement, polyhydramnios, breech presentation, and clubfeet. Two pregnancies were terminated. Four live-born patients had postnatal features typical of nemaline myopathy 8. The length of survival ranged from 49 days to 17 months, with respiratory failure and infections being the principal causes of death. Haplotype analysis in three patients with homozygous mutation showed a shared haplotype block of 1.1727 cM spanning over the c.1516A>C variant, suggesting it is a southern Chinese-specific founder mutation.
Revvity Omics, Revvity	RCV001050162	SCV002016383	pathogenic	Nemaline myopathy 8	2021-09-09	criteria provided, single submitter	clinical testing
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV001050162	SCV002496408	pathogenic	Nemaline myopathy 8	2022-01-01	criteria provided, single submitter	clinical testing
3billion	RCV001050162	SCV002572633	pathogenic	Nemaline myopathy 8	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.11). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000846771). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (3billion dataset / VCV000846771). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001050162	SCV005085971	pathogenic	Nemaline myopathy 8	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nemaline myopathy 8 (MIM#615348). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to proline. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 26 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Kelch_1 domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple patients with nemaline myopathy and is a recurrent variant in Chinese population (ClinVar, PMIDs: 31360996, 35379254). (SP) 1102 - Strong phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign