Submissions for variant NM_002180.3(IGHMBP2):c.767C>G (p.Ala256Gly)

gnomAD frequency: 0.00065  dbSNP: rs148095551

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202957	SCV000257913	uncertain significance	not specified	2015-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000767054	SCV000292584	uncertain significance	not provided	2020-07-27	criteria provided, single submitter	clinical testing	Observed in 2 unrelated patients with IGHMBP2-related disorders in published literature (Gonzaga-Jauregui et al., 2015; Bansagi et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28251916, 26257172, 32376792)
Illumina Laboratory Services, Illumina	RCV000330776	SCV000373766	uncertain significance	Autosomal recessive distal spinal muscular atrophy 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000528045	SCV000642368	likely benign	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000767054	SCV001148359	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173346	SCV001336434	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001336447	SCV001529832	uncertain significance	Charcot-Marie-Tooth disease axonal type 2S	2018-03-26	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000767054	SCV002541160	uncertain significance	not provided	2021-04-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399756	SCV002674218	uncertain significance	Inborn genetic diseases	2022-01-26	criteria provided, single submitter	clinical testing	The p.A256G variant (also known as c.767C>G), located in coding exon 6 of the IGHMBP2 gene, results from a C to G substitution at nucleotide position 767. The alanine at codon 256 is replaced by glycine, an amino acid with similar properties. This alteration was reported in a patient with congenital hypomyelinating neuropathy who also had two additional alterations in IGHMBP2 although parental samples were unavailable to determine phase (Gonzaga-Jauregui C et al. Cell Rep, 2015 Aug;12:1169-83). This alteration was also reported in the heterozygous state in a young boy with features of distal hereditary motor neuronopathy (Bansagi B et al. Neurology, 2017 Mar;88:1226-1234), and in an individual with a diagnosis of Charcot-Marie-Tooth disease type 2 with limited clinical detail (Antoniadi T et al. BMC Med Genet, 2015 Sep;16:84). 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	RCV000767054	SCV003813329	uncertain significance	not provided	2023-11-28	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000528045	SCV001749698	not provided	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-07-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.