Submissions for variant NM_001101362.3(KBTBD13):c.769G>C (p.Asp257His)

gnomAD frequency: 0.00020  dbSNP: rs568675071

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001087024	SCV000393289	benign	Nemaline myopathy 6	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000498308	SCV000590022	uncertain significance	not provided	2017-06-02	criteria provided, single submitter	clinical testing	The D257H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D257H variant is observed in 11/980 (1.12%) alleles from individuals of East Asian background in large population cohorts, which is greater than expected for this disorder (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087024	SCV000761552	benign	Nemaline myopathy 6	2024-01-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003940234	SCV004761937	benign	KBTBD13-related disorder	2019-10-31	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).