ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1488C>A (p.Cys496Ter) (rs145226920)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219401 SCV000278983 pathogenic not provided 2017-11-08 criteria provided, single submitter clinical testing The C496X nonsense variant has been reported in association with SMARD1 in multiple patients who have a second pathogenic variant on the other allele (Grohmann et al., 2003; Maystadt et al., 2004; Litvineko et al., 2014). It has also been reported in a patient with CMT2 who had another pathogenic variant on the opposite allele (Cottenie et al., 2014). The C496X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, C496X is interpreted to be a pathogenic variant.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235082 SCV000292359 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1 2015-08-18 criteria provided, single submitter research This variant has been previously reported as disease-causing and was identified in trans with a predicted pathogenic variant in an individual with congenital hypotonia.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000219401 SCV000336679 pathogenic not provided 2015-10-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000219401 SCV000604018 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing The p.Cys496Ter variant has been reported in homozygous form as well as in compound heterozygous form together with missense or other nonsense variants in infants with spinal muscular atrophy with respiratory distress type 1 (SMARD1) with age onset of respiratory distress ranging from 3 - 91 days after birth (Grohmann 2003). Many affected infants presented with intrauterine growth restriction, decreased fetal movements, weak cry, congenital foot deformities due to early involvement of distal muscles of the lower limbs, eventration of the diaphragm due to a diaphragmatic paralysis, involvement of the autonomic nervous system, neurogenic changes in electromyography, decrease in motor nerve conduction velocity and absence of motor response after maximum stimulation, as well as fiber hypertrophy and atrophy on muscle biopsy (Grohmann 2003). Furthermore, Maystad et al. (2004) reported an infant who presented at 2 months with muscular weakness, at 2.5 month with respiratory distress and who died at 6 months. He carried the same p.Cys496Ter variant but a second IGHMBP2 variant was not identified (Maystad 2004). Additionally, Litvinenko et al. (2014) reported two infant siblings with p.Cys496Ter and Gln260fs compound heterozygous variants with severe spinal muscular atrophy respiratory distress 1, persistent eventration of the right hemidiaphragm, hypotonia due to hypo- and areflexia, complete paralysis of the limbs and mild contractures, electromyography showing active denervation, and total absence of IGHMBP2 enzyme activity. Finally, Cottenie et al. (2014) reported a 15 year old male with foot drop (first presenting at age 4), limb weakness, and ankle foot orthoses, who carried p.Cys496Ter and a missense variant.
Invitae RCV000539394 SCV000642306 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys496*) in the IGHMBP2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs145226920, ExAC 0.06%). This variant has been identified in the homozygous or compound heterozygous state with other IGHMBP2 variants in individuals affected with spinal muscular atrophy with respiratory distress 1 (SMARD1) (PMID: 14681881, 19157874, 14506069, 26257172, 23449687). This variant has also been identified in the compound heterozygous state in an individual affected with Charcot-Marie-Tooth disease type 2 (CMT2) (PMID: 25439726). ClinVar contains an entry for this variant (PMID: 234316). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780353 SCV000917543 pathogenic Charcot-Marie-Tooth disease, axonal, type 2S 2018-10-24 criteria provided, single submitter clinical testing Variant summary: IGHMBP2 c.1488C>A (p.Cys496X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 259950 control chromosomes (gnomAD). The variant, c.1488C>A, has been reported in the literature in one compound heterozygote affected with Charcot-Marie-Tooth disease type 2B2 (CMT2) (Cottenie_2014) and more frequently in compound heterozygotes and homozygotes affected with spinal muscular atrophy with respiratory distress type 1 (SMARD1)( Grohmann_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for CMT2.

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