Submissions for variant NM_002180.3(IGHMBP2):c.1064C>T (p.Ala355Val)

gnomAD frequency: 0.00231  dbSNP: rs142062146

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087969	SCV000642294	likely benign	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2024-12-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727033	SCV000705058	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000727033	SCV000728569	likely benign	not provided	2021-02-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727033	SCV001148360	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	IGHMBP2: BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727033	SCV001159710	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	The IGHMBP2 c.1064C>T; p.Ala355Val variant (rs142062146), to our knowledge, is not reported in an individual with neuronopathy or CMT but is reported in the literature in the homozygous state in an individual who was affected with schizophrenia/schizoaffective disorder; however, the contribution of this variant to the phenotype is not known (Need 2012). This variant is reported in ClinVar (Variation ID: 466572) and is found in the African population with an overall allele frequency of 0.76% (189/24,948 alleles) in the Genome Aggregation Database. The alanine at codon 355 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.585). Although there is no evidence for pathogenicity, we cannot rule out the possibility, therefore, the significance of the variant is uncertain at this time. REFERENCE Need et al. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet. 2012 Aug 10;91(2):303-12.
Illumina Laboratory Services, Illumina	RCV001109641	SCV001267002	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174193	SCV001337319	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002413540	SCV002716443	likely benign	Inborn genetic diseases	2019-11-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV004553226	SCV004743780	benign	IGHMBP2-related disorder	2020-02-05	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).