Submissions for variant NM_001101362.3(KBTBD13):c.742C>T (p.Arg248Cys)

dbSNP: rs200549195

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000639957	SCV000393287	likely benign	Nemaline myopathy 6	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639957	SCV000761543	likely benign	Nemaline myopathy 6	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001579432	SCV001936467	benign	not provided	2018-11-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31127727)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000414516	SCV002766136	uncertain significance	not specified	2024-07-26	criteria provided, single submitter	clinical testing	Variant summary: KBTBD13 c.742C>T (p.Arg248Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five 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 153572 control chromosomes. This frequency does not allow conclusions about variant significance, although it seems high for an autosomal dominant disease. c.742C>T has been reported in the literature in individuals reportedly affected with features of Nemaline Myopathy 6 (Bouman_2021, Westra_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Nemaline Myopathy 6. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31127727, 33693846). ClinVar contains an entry for this variant (Variation ID: 316744). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000414516	SCV000490573	uncertain significance	not specified	2016-03-25	flagged submission	clinical testing	A variant of uncertain significance has been identified in the KBTBD13 gene. The R248C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R248C variant was not observed with any significant frequency in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R248C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same position (R248S) has been reported in the Human Gene Mutation Database in association with nemaline myopathy type 6 (Stenson et al., 2014; Sambuughin et al., 2010). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579432	SCV001807213	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579432	SCV001960015	uncertain significance	not provided		no assertion criteria provided	clinical testing