Submissions for variant NM_024577.3(SH3TC2):c.1942C>T (p.Arg648Trp) (rs537049075)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV001095110	SCV000454549	likely benign	Charcot-Marie-Tooth disease, type 4C	2018-01-12	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.
Illumina Clinical Services Laboratory,Illumina	RCV000268641	SCV000454550	likely benign	Mononeuropathy of the median nerve, mild	2018-01-12	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	RCV000360932	SCV001003297	likely benign	Charcot-Marie-Tooth disease type 4	2019-12-31	criteria provided, single submitter	clinical testing
Diagnostics Lab (ASPIRE), CSIR - Centre for Cellular and Molecular Biology	RCV001030761	SCV001190224	uncertain significance	Hereditary motor and sensory neuropathy	2019-12-24	criteria provided, single submitter	clinical testing	The c.1942C>T variant is not present in publicly available database like Exome Variant Server (EVS), however present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at a low minor allele frequency (MAF<0.001), including one homozygote. The variant is present in our in-house exome database in heterozygous state (MAF~0.005). The variant was reported to ClinVar (Accession ID: VCV000351908.2) with conflicting interpretation of pathogenicity (likely benign/uncertain significance). In-silico pathogenicity prediction programslike SIFT, PolyPhen-2, MutationTaster2, CADD etc. predicted this variant as likely deleterious, however functional assay was not done to prove this. Due to lack of enough evidence the variant has been classified as uncertain significance.

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