Submissions for variant NM_002180.2(IGHMBP2):c.1336C>T (p.Gln446Ter) (rs372181708)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760424	SCV000890305	likely pathogenic	not provided	2018-11-27	criteria provided, single submitter	clinical testing	The Q446X variant has been previously reported in an individual with SMARD1 who harbored a second IGHMBP2 variant (Jedrzejowska et al., 2014). The Q446X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Invitae	RCV000791593	SCV000930850	pathogenic	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2019-10-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln446*) in the IGHMBP2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs372181708, ExAC 0.002%). This variant has been observed in an individual affected with spinal muscular atrophy with respiratory distress type 1 (SMARD1) (PMID: 24388491). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000826144	SCV000967674	pathogenic	Distal spinal muscular atrophy	2018-07-18	criteria provided, single submitter	clinical testing	The p.Gln446X variant in IGHMBP2 has been previously reported in one compound he terozygous individual with spinal muscular atrophy with respiratory distress (SM ARD1) who also carried a de novo missense allele (Jedrzejowska 2014). This varia nt has been identified in 3/110614 European chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs372181708). This n onsense variant leads to a premature termination codon at position 446, which is predicted to lead to a truncated or absent protein. Complete loss of IGHMBP2 fu nction is an established disease mechanism for SMARD1. In summary, this variant meets criteria to be classified as pathogenic for SMARD1 in an autosomal recessi ve manner. ACMG/AMP criteria applied: PVS1, PM3_Supporting, PM2.
Inherited Neuropathy Consortium	RCV000789344	SCV000928697	uncertain significance	Autosomal dominant distal hereditary motor neuropathy		no assertion criteria provided	literature only