Submissions for variant NM_001005361.3(DNM2):c.1070C>T (p.Ser357Phe)

dbSNP: rs1064793101

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485589	SCV000564942	likely pathogenic	not provided	2014-09-18	criteria provided, single submitter	clinical testing	A novel S357F variant that is likely pathogenic has been identified in the DNM2 gene. The S357F variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The S357F 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense mutation in the adjacent amino acid (G358R) has been reported in the Human Gene Mutation Database (HGMD) is association with CMT (Stenson et al., 2009). Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	RCV002221154	SCV001976634	likely pathogenic	Charcot-Marie-Tooth disease dominant intermediate B	2021-07-20	criteria provided, single submitter	research	The p.Ser357Phe variant in the DNM2 gene has recently been described in the literature, classified as likely pathogenic, in a large Italian family with CMT2M (PMID: 33459893). This variant is not present in population databases (GnomAD and ABraOM), suggesting it is not a common benign variant in these populations. ClinVar classifies this variant as likely pathogenic (Variation ID: 418164), 1 star. This variant replaces serine with phenylalanine at codon 357 of the DNM2 protein, which is highly conserved across different species. This variant is in an important functional domain of the protein (Middle domain). Our lab found it in one family, all in heterozygous, and the index patient is a 16-years-old female with a severe CMT2 phenotype with motor predominance. Her mother, aunt, and cousin have the same variant and are also affected. So, this variant segregates with the family phenotype (CMT2) in an autosomal dominant inheritance. In addition, two other variants in adjacent amino acids (p.Gly358Arg and p.Gly359Asp) have already been reported in the literature, classified as pathogenic, related to the phenotype of CMT2M and CMTiB, respectively (PMID: 28971531; PMID: 19502294). In summary, the p.Ser357Phe meets our criteria to be classified as likely pathogenic.
Athena Diagnostics	RCV000485589	SCV004229591	likely pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	This variant has been identified in multiple individuals with Charcot-Marie-Tooth disease and appears to segregate with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).