Submissions for variant NM_002180.2(IGHMBP2):c.767C>G (p.Ala256Gly) (rs148095551)

Total submissions: 8

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 Clinical Services Laboratory,Illumina	RCV000330776	SCV000373766	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 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	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2020-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with glycine at codon 256 of the IGHMBP2 protein (p.Ala256Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs148095551, ExAC 0.2%). This variant has been observed in an individual affected with congenital hypomyelinating neuropathy (PMID: 26257172). However this individual carried 2 additional rare missense variants in IGHMBP2, making the role of this c.767C>G variant unclear. This variant has also been reported in the heterozygous state in one individual affected with hereditary motor neuropathy (PMID: 28251916). ClinVar contains an entry for this variant (Variation ID: 218603). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000767054	SCV001148359	uncertain significance	not provided	2016-06-01	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].
GenomeConnect - Invitae Patient Insights Network	RCV000528045	SCV001749698	not provided	Spinal muscular atrophy, distal, autosomal recessive, 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.