Submissions for variant NM_002180.2(IGHMBP2):c.439C>T (p.Arg147Ter) (rs1324667543)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623030	SCV000741689	pathogenic	Inborn genetic diseases	2016-07-26	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
GeneDx	RCV000760313	SCV000890168	pathogenic	not provided	2018-11-19	criteria provided, single submitter	clinical testing	The R147X variant in the IGHMBP2 gene has been reported previously in association with spinal muscular atrophy with respiratory distress type 1 (SMARD1) in patients with a second IGHBMP2 pathogenic variant on the opposite allele (Grohmann et al., 2003; Jedrzejowska et al., 2014; San Millan et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R147X variant is observed in 1/9850 (0.01%) alleles in individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). We interpret R147X as a pathogenic variant.
Invitae	RCV000806942	SCV000946966	pathogenic	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2019-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg147*) in the IGHMBP2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another IGHMBP2 variant in several individuals affected with autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) (PMID: 14681881, 26709713, 24388491). ClinVar contains an entry for this variant (Variation ID: 521206). Loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000760313	SCV001245952	pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789338	SCV000928691	uncertain significance	Autosomal dominant distal hereditary motor neuropathy		no assertion criteria provided	literature only

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