Submissions for variant NM_024577.3(SH3TC2):c.3380G>A (p.Arg1127Gln) (rs139192433)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214292	SCV000279172	uncertain significance	not provided	2017-06-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SH3TC2 gene. This variant was observed in the heterozygous state in 3 individuals with symptoms of CMT1 and was described as being a variant of unknown significance (Antoniadi et al., 2015). A missense variant in the same residue (R1127W) has been reported in the Human Gene Mutation Database in association with SH3TC2-related disease (Stenson et al., 2014). The 1000 Genomes Project reports R1127Q was observed in 2/182 (1.1%) alleles from individuals of British background, and the NHLBI Exome Sequencing Project reports R1127Q was observed in 19/8600 (0.2%) alleles from individuals of European background. The R1127Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina	RCV001095006	SCV000454522	uncertain significance	Charcot-Marie-Tooth disease, type 4C	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV000355518	SCV000454523	likely benign	Mononeuropathy of the median nerve, mild	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000473910	SCV000546363	likely benign	Charcot-Marie-Tooth disease type 4	2019-12-31	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000214292	SCV001145612	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000214292	SCV001154549	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001173826	SCV001336942	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing