Submissions for variant NM_000530.8(MPZ):c.434_437del (p.Tyr145fs)

dbSNP: rs1553259643

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638153	SCV000759639	pathogenic	Charcot-Marie-Tooth disease, type I	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr145Serfs*16) in the MPZ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPZ are known to be pathogenic (PMID: 14711881). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25614874). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MPZ variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 11,906 individuals referred to our laboratory for MPZ testing. ClinVar contains an entry for this variant (Variation ID: 531677). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV001289099	SCV001476690	pathogenic	not provided	2020-04-30	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene
Ambry Genetics	RCV002528900	SCV003549721	pathogenic	Inborn genetic diseases	2022-11-15	criteria provided, single submitter	clinical testing	The c.434_437delATGT (p.Y145Sfs*16) alteration, located in exon 3 (coding exon 3) of the MPZ gene, consists of a deletion of 4 nucleotides from position 434 to 437, causing a translational frameshift with a predicted alternate stop codon after 16 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported once in a large cohort of patients with features of Charcot-Marie-Tooth disease (DiVincenzo, 2014). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004533337	SCV004112953	likely pathogenic	MPZ-related disorder	2022-11-07	criteria provided, single submitter	clinical testing	The MPZ c.434_437delATGT variant is predicted to result in a frameshift and premature protein termination (p.Tyr145Serfs*16). This variant was reported in an individual with Charcot-Marie-Tooth disease (Supplemental Table 5, DiVincenzo et al. 2014. PubMed ID: 25614874). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MPZ are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Inherited Neuropathy Consortium	RCV000790074	SCV000929464	pathogenic	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV003483698	SCV004228729	not provided	Charcot-Marie-Tooth disease type 2I; Charcot-Marie-Tooth disease type 2J; Charcot-Marie-Tooth disease type 1B; Charcot-Marie-Tooth disease dominant intermediate D		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 04-10-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.