Submissions for variant NM_002180.2(IGHMBP2):c.1693G>A (p.Asp565Asn) (rs770111639)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biochemistry Laboratory of CDMU,Chengde Medical University	RCV000768429	SCV000899184	likely pathogenic	Charcot-Marie-Tooth disease, axonal, type 2S		no assertion criteria provided	case-control
Inherited Neuropathy Consortium	RCV000790283	SCV000929687	uncertain significance	Distal spinal muscular atrophy		no assertion criteria provided	literature only
Invitae	RCV000705582	SCV000834584	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2018-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 565 of the IGHMBP2 protein (p.Asp565Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs770111639, ExAC 0.005%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with distal hereditary motor neuropathy, type VI (PMID: 15108294). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has been reported in combination with another IGHMBP2 variant in an individual affected with distal hereditary motor neuropathy, type VI (PMID: 22157136, 14681881). Experimental studies have shown that this missense change results in abolished helicase activity of the encoded IGHMBP2 protein (PMID: 19158098, 22157136). 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.