Submissions for variant NM_152393.4(KLHL40):c.968T>G (p.Ile323Ser)

gnomAD frequency: 0.00043  dbSNP: rs146161469

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000401225	SCV000329380	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549336	SCV000654262	uncertain significance	Nemaline myopathy 8	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 323 of the KLHL40 protein (p.Ile323Ser). This variant is present in population databases (rs146161469, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with KLHL40-related conditions. ClinVar contains an entry for this variant (Variation ID: 279825). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000401225	SCV004226092	uncertain significance	not provided	2022-02-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525913	SCV005040579	uncertain significance	not specified	2024-03-28	criteria provided, single submitter	clinical testing	Variant summary: KLHL40 c.968T>G (p.Ile323Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251450 control chromosomes (gnomAD). To our knowledge, no occurrence of c.968T>G in individuals affected with Nemaline Myopathy 8 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 279825). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000401225	SCV001550257	uncertain significance	not provided		no assertion criteria provided	clinical testing	The KLHL40 p.Ile323Ser variant was not identified in the literature but was identified in dbSNP (ID: rs146161469) and ClinVar (classified as uncertain significance by Invitae for Nemaline myopathy 8 and GeneDx). The variant was identified in control databases in 108 of 282838 chromosomes at a frequency of 0.0003818 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 96 of 129144 chromosomes (freq: 0.000743), Other in 4 of 7226 chromosomes (freq: 0.000554), European (Finnish) in 3 of 25124 chromosomes (freq: 0.000119), Latino in 4 of 35440 chromosomes (freq: 0.000113) and African in 1 of 24966 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. Although the p.Ile323 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.