Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000800244 | SCV000939944 | pathogenic | Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S | 2018-09-25 | 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with spinal muscular atrophy with respiratory distress type I (SMARD1) (PMID: 16765827). This variant has also been observed in combination with another IGHMBP2 variant in other individuals affected with SMARD1 and Charcot-Marie-Tooth disease type 2 (PMID: 28397221, 28065684). These findings are consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.2355_2356delG in the literature. 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. |
| 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 |