Total submissions: 3
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. |
Gene |
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 |