Submissions for variant NM_002180.3(IGHMBP2):c.127C>T (p.Arg43Ter)

gnomAD frequency: 0.00003  dbSNP: rs200089714

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221711	SCV000271379	pathogenic	Distal spinal muscular atrophy	2015-03-11	criteria provided, single submitter	clinical testing	The p.Arg43X variant in IGHMBP2 has been previously reported in one compound het erozygous individual with spinal muscular atrophy with respiratory distress (SMA RD1; Pitt 2003). It has also been identified in 0.01% (5/66736) European chromos omes by the Exome Aggregation Consortium (http://exac.broadinstitute.org; dbSNP rs200089714). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Th is nonsense variant leads to a premature termination codon at position 43, which is predicted to lead to a truncated or absent protein. Complete loss of IGHMBP2 function is an established disease mechanism for SMARD1. In summary, this varia nt meets our criteria to be classified as pathogenic for SMARD1 in an autosomal recessive manner (www.partners.org/personalizedmedicine/lmm).
Eurofins Ntd Llc (ga)	RCV000482426	SCV000345519	pathogenic	not provided	2016-09-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000482426	SCV000565070	pathogenic	not provided	2022-04-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14506069)
Invitae	RCV001059408	SCV001224032	pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg43*) in the IGHMBP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). This variant is present in population databases (rs200089714, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with severe infantile neuropathy with diaphragmatic weakness (PMID: 14506069). ClinVar contains an entry for this variant (Variation ID: 228355). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000482426	SCV001249649	pathogenic	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335233	SCV004046336	pathogenic	IGHMBP2-related disorders		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 2 of 15 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in a patient with early onset diaphragmatic palsy in association with a progressive neuropathy (PMID: 14506069). Loss-of-function variation in IGHMBP2 is an established mechanism of disease (PMID: 14681881, 25439726, 25568292). The c.127C>T (p.Arg43Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (10/282866) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.127C>T (p.Arg43Ter) variant is classified as Pathogenic.