Submissions for variant NM_001005360.2(DNM2):c.2576_2581del (p.Thr859_Ile860del) (rs876661117)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422170	SCV000279572	uncertain significance	not provided	2016-12-16	criteria provided, single submitter	clinical testing	The c.2576_2581delCCATTA variant in the DNM2 gene has been reported in the heterozygous state, in a different transcript (NM_004945) with the alternate nomenclature, p.T855_I856del, in a 67 year old individual with infantile onset distal lower limb muscle weakness and atrophy, gait difficulties, lower limb cramps and bilateral foot drop with family history of a similarly affected sibling and parent (Claeys et al., 2009). The c.2576_2581delCCATTA variant was not observed at any significant frequency in approximately 6500 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 c.2576_2581delCCATTA variant is an in-frame deletion that results in the loss of two amino acid residues, denoted p.Thr859_Ile860del. Of the deleted residues, the first is in a position that is conserved across species and the second is in a position where amino acids with similar properties to threonine are tolerated across species. Therefore, we interpret c.2576_2581delCCATTA as a variant of unknown significance.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000422170	SCV000511354	uncertain significance	not provided	2016-11-22	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Invitae	RCV001216040	SCV001387812	uncertain significance	Charcot-Marie-Tooth disease, dominant intermediate B	2019-06-14	criteria provided, single submitter	clinical testing	This variant, c.2576_2581del, results in the deletion of 2 amino acid(s) of the DNM2 protein (p.Thr859_Ile860del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs778350664, ExAC 0.004%). This variant has been observed in an individual affected with Charcot-Marie-Tooth disease (PMID: 19502294). This variant is also known as c.2564_2569delCCATTA, Thr855_Ile856del in the literature. ClinVar contains an entry for this variant (Variation ID: 234609). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.