Submissions for variant NM_152393.4(KLHL40):c.931C>A (p.Arg311Ser)

dbSNP: rs763283033

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541547	SCV000654261	pathogenic	Nemaline myopathy 8	2023-01-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg311 amino acid residue in KLHL40. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23746549). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 474339). This missense change has been observed in individual(s) with clinical features of nemaline myopathy (PMID: 26578207; Invitae). This variant is present in population databases (rs763283033, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 311 of the KLHL40 protein (p.Arg311Ser).
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV000541547	SCV000864074	likely pathogenic	Nemaline myopathy 8	2017-01-01	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000541547	SCV003810071	uncertain significance	Nemaline myopathy 8	2022-05-03	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000541547	SCV004171836	likely pathogenic	Nemaline myopathy 8		criteria provided, single submitter	clinical testing	The missense c.931C>A (p.Arg311Ser) variant in KLHL40 gene has been reported previously in homozygous state in individuals affected nemaline myopathy (Ravenscroft et al. 2014; Todd et al. 2015). Another missense [c.932G>T | p.Arg311Leu] variant at this residue has previously been reported in trans with a pathogenic missense [c.1516A>C | p.Thr506Pro] variant (Ravenscroft et al. 2013; Todd et al. 2015). The p.Arg311Ser variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid change p.Arg311Ser in KLHL40 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 311 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000541547	SCV005086981	pathogenic	Nemaline myopathy 8	2023-07-17	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 arginine to serine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (Highest allele count in v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg311Leu) has been reported in one compound heterozygote and one homozygote with nemaline myopathy (PMID: 23746549, 30665247). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. One homozygote was reported from a cohort diagnosed with fetal akinesia deformation sequence, arthrogryposis, or a severe congenital myopathy (PMID: 26578207). Two homozygotes with features including myopathy, neonatal hypotonia and respiratory distress were reported in DECIPHER. In addition, this variant has been classified as VUS in ClinVar. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 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
GeneDx	RCV004777734	SCV005390514	uncertain significance	not provided	2024-05-01	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: 26578207, 23746549)