Submissions for variant NM_000530.8(MPZ):c.431del (p.Leu144fs) (rs1182353109)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000778189	SCV000914353	uncertain significance	MPZ-Related Disorders	2018-08-27	criteria provided, single submitter	clinical testing	The MPZ c.431delT (p.Leu144ArgfsTer18) variant results in a frameshift and is predicted to result in a premature truncation of the protein. The p.Leu144ArgfsTer18 variant has been reported in one study in which it was identified in a heterozygous state in one individual with Charcot-Marie-Tooth type 1A (Simpson et al. 2010). This variant has not been reported in individuals with other MPZ-related disorders including Charcot-Marie-Tooth, intermediate, congenital hypomyelinating neuropathy, congenital hypomyelination, and Roussy-Levy syndrome. Control data are not available for the p.Leu144ArgfsTer18 variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or Genome Aggregation Database in a region of good sequencing coverage so is presumed to be rare. Based on limited clinical evidence and the potential impact of frameshift variants, the p.Leu144ArgfsTer18 variant is classified as a variant of unknown significance but suspicious for pathogenicity for MPZ-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000797748	SCV000937327	pathogenic	Charcot-Marie-Tooth disease, type I	2019-02-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu144Argfs*18) in the MPZ gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Charcot-Marie-Tooth disease type 1 (PMID: 20516806). Loss-of-function variants in MPZ are known to be pathogenic (PMID: 14711881). For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium	RCV000789477	SCV000928833	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only

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