ClinVar Miner

Submissions for variant NM_002180.3(IGHMBP2):c.165G>C (p.Gln55His)

gnomAD frequency: 0.00044  dbSNP: rs201692151
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489846 SCV000577545 likely benign not provided 2021-02-22 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25025039, 32376792)
Invitae RCV001083586 SCV000642316 likely benign Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S 2024-01-29 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000489846 SCV001148357 uncertain significance not provided 2017-01-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre RCV001173342 SCV001336430 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000489846 SCV001716100 uncertain significance not provided 2020-12-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222528 SCV002500219 likely benign not specified 2022-03-08 criteria provided, single submitter clinical testing Variant summary: IGHMBP2 c.165G>C (p.Gln55His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251490 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in IGHMBP2 causing Charcot-Marie-Tooth Disease, Axonal, Type 2S, allowing no conclusion about variant significance. Although reported as a VUS in settings of multigene panel testing among cohorts of individuals with suspected Charcot-Marie-Tooth (CMT) disease (example, Volodarsky_2021), to our knowledge, no penetrant association of c.165G>C in individuals affected with Charcot-Marie-Tooth Disease, Axonal, Type 2S and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV002404282 SCV002707523 uncertain significance Inborn genetic diseases 2022-05-10 criteria provided, single submitter clinical testing The p.Q55H variant (also known as c.165G>C), located in coding exon 2 of the IGHMBP2 gene, results from a G to C substitution at nucleotide position 165. The glutamine at codon 55 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV000489846 SCV003813341 uncertain significance not provided 2020-01-10 criteria provided, single submitter clinical testing

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