Submissions for variant NM_000530.8(MPZ):c.313C>A (p.Pro105Thr) (rs121913609)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223657	SCV000279620	likely pathogenic	not provided	2016-01-18	criteria provided, single submitter	clinical testing	The P105T variant in the MPZ gene has been reported previously in two brothers with late-onset Charcot-Marie-Tooth type 2 and hearing impairment (Kabzinska et al., 2007). The P105T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P105T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. This substitution occurs at a position that is conserved across species. Additionally, multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
OMIM	RCV000015263	SCV000035522	pathogenic	Charcot-Marie-Tooth disease type 2J	2007-09-15	no assertion criteria provided	literature only