ClinVar Miner

Submissions for variant NM_002180.3(IGHMBP2):c.2356del (p.Ala786fs)

dbSNP: rs750994603
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000800244 SCV000939944 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.Ala786Profs*45) 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 (rs750994603, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease type 2 and/or spinal muscular atrophy with respiratory distress type I (PMID: 16765827, 28065684, 28397221). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2355_2356delG. ClinVar contains an entry for this variant (Variation ID: 637908). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001008804 SCV001168602 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing The c.2356delG variant in the IGHMBP2 gene has been reported previously in association with IGHMBP2-related disorders with present in trans with another disease-causing variant (Wong et al., 2006; Liu et al., 2017). The c.2356delG variant causes a frameshift starting with codon Alanine 786, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 45 of the new reading frame, denoted p.Ala786ProfsX45. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2356delG variant is observed in 5/18,844 (0.026%) alleles from individuals of East Asian background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.2356delG as a pathogenic variant.
Inherited Neuropathy Consortium RCV000790284 SCV000929688 uncertain significance Distal spinal muscular atrophy no assertion criteria provided literature only

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