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

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Division of Genomic Diagnostics,The 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	2018-11-28	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the IGHMBP2 gene. The A256G variant waspreviously reported in an individual with autosomal recessive distal hereditary motor neuropathy typeVI; this patient also harbored two other variants in IGHMBP2 and parental samples were not available for segregation analysis (Gonzaga-Jauregui et al., 2015). The A256G variant has also been reported in the heterozygous state in a child reported to have a phenotype fitting of an IGHMBP2-related disorder; however, detailed information was not provided (Bansagi et al., 2017). The A256G variant is observed in 54/30782 (0.2%) alleles from individuals of South Asian background (Lek et al., 2016). The A256G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
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	2019-12-17	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