Submissions for variant NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter)

gnomAD frequency: 0.00016  dbSNP: rs145226920

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000219401	SCV000278983	pathogenic	not provided	2022-10-27	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; This variant is associated with the following publications: (PMID: 23449687, 25439726, 15108294, 25525159, 29431110, 26709713, 31827005, 31589614, 33442022, 32573669, 32376792, 14681881, 34726235)
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000235082	SCV000292359	pathogenic	Autosomal recessive distal spinal muscular atrophy 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.
Eurofins Ntd Llc (ga)	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	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2024-01-23	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. Loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). This variant is present in population databases (rs145226920, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with spinal muscular atrophy with respiratory distress 1 (SMARD1) (PMID: 14506069, 14681881, 19157874, 23449687, 26257172). ClinVar contains an entry for this variant (Variation ID: 234316). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Mendelics	RCV000235082	SCV001138369	pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2019-05-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000235082	SCV001245043	pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, axonal, type 2S (MIM#616155), and distal hereditary motor neuronopathy, type VI (MIM#604320). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (42 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic in individuals with either spinal muscular atrophy with respiratory distress (SMARD) or Charcot-Marie-Tooth (CMT) (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both compound heterozygous and homozygous individuals with SMARD, and rarely in individuals with CMT (ClinVar, PMID: 25439726, PMID: 30598237). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000539394	SCV001251514	likely pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S		criteria provided, single submitter	research	The IGHMBP2 c.1488C>A (p.C496*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been observed in the compound heterozygous state in individuals with Charcot-Marie-Tooth disease type 2S or spinal muscular atrophy with respiratory distress type 1 (SMARD1) (PMID: 14506069; 15108294; 19157874; 23449687; 25439726).
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172566	SCV001335628	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000219401	SCV002023141	pathogenic	not provided	2022-05-16	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV002277579	SCV002564536	pathogenic	Neurodevelopmental disorder	2022-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390588	SCV002700863	pathogenic	Inborn genetic diseases	2020-03-23	criteria provided, single submitter	clinical testing	The p.C496* pathogenic mutation (also known as c.1488C>A), located in coding exon 10 of the IGHMBP2 gene, results from a C to A substitution at nucleotide position 1488. This changes the amino acid from a cysteine to a stop codon within coding exon 10. This alteration has been detected in the homozygous and compound heterozygous states in patients with spinal muscular atrophy with respiratory distress type 1 (SMARD1) (Grohmann K et al. Ann. Neurol., 2003 Dec;54:719-24; Joseph S et al. Neuromuscul. Disord., 2009 Mar;19:193-5; Pitt M et al. Brain, 2003 Dec;126:2682-92; San Millan B et al. Clin. Neuropathol.;35:58-65). This alteration has also been detected in the compound heterozygous state in a patient with Charcot-Marie-Tooth disease, type 2 (Cottenie E et al. Am. J. Hum. Genet., 2014 Nov;95:590-601). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000219401	SCV001808620	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000219401	SCV001920518	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000219401	SCV001955126	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000219401	SCV001971384	pathogenic	not provided		no assertion criteria provided	clinical testing