Submissions for variant NM_014629.4(ARHGEF10):c.2197C>T (p.His733Tyr) (rs147531758)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755828	SCV000883416	uncertain significance	not provided	2017-08-23	criteria provided, single submitter	clinical testing	The p.His733Tyr variant (rs147531758) has been reported in the medical literature in a single individual with Charcot-Marie-Tooth (CMT) type 2 who also had a potentially pathogenic variant in the LMNA gene (Høyer 2014). It has also been identified by our laboratory in four individuals without a reported diagnosis of CMT, is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.19% in the non-Finnish European population (identified in 244 out of 126,604 chromosomes; 1 homozygote), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 157538). The histidine at codon 733 is highly conserved considering 12 species up to zebrafish (Alamut software v2.9.0); however, it is a tyrosine in armadillos, suggesting that this substitution may be evolutionary tolerated. Computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerate, PolyPhen2: probably damaging, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.His733Tyr variant cannot be determined with certainty.
Dept. of Medical Genetics, Telemark Hospital Trust	RCV000144885	SCV000118596	uncertain significance	Charcot-Marie-Tooth disease	2013-11-01	no assertion criteria provided	research