ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1060G>A (p.Gly354Ser) (rs886043773)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000596478 SCV000701225 likely pathogenic not provided 2016-10-12 criteria provided, single submitter clinical testing
Invitae RCV000819925 SCV000960612 likely 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 replaces glycine with serine at codon 354 of the IGHMBP2 protein (p.Gly354Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 7 of the IGHMBP2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with spinal muscular atrophy with respiratory distress, type I (SMARD1) (PMID: 22157136). This variant has also been observed in combination with another IGHMBP2 variant in an individual affected with SMARD1 (PMID: 16964485). These finding are consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 287977). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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