Submissions for variant NM_030962.4(SBF2):c.3824G>A (p.Arg1275His)

gnomAD frequency: 0.00059  dbSNP: rs150028248

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196586	SCV000255136	uncertain significance	Charcot-Marie-Tooth disease type 4	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1275 of the SBF2 protein (p.Arg1275His). This variant is present in population databases (rs150028248, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 216776). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SBF2 protein function with a positive predictive value of 80%. 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.
GeneDx	RCV000215903	SCV000279164	uncertain significance	not provided	2025-02-14	criteria provided, single submitter	clinical testing	Identified in two individuals with suspected CMT, however information regarding the presence or absence of a second SBF2 variant was not provided (PMID: 32376792); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32211398, 33726816, 32376792)
Illumina Laboratory Services, Illumina	RCV001094184	SCV000375045	uncertain significance	Charcot-Marie-Tooth disease type 4B2	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.
Athena Diagnostics	RCV000215903	SCV001145365	uncertain significance	not provided	2021-09-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000215903	SCV001148187	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172794	SCV001335863	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818491	SCV002066530	uncertain significance	not specified	2019-03-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002363019	SCV002623782	uncertain significance	Inborn genetic diseases	2022-01-11	criteria provided, single submitter	clinical testing	The p.R1275H variant (also known as c.3824G>A), located in coding exon 29 of the SBF2 gene, results from a G to A substitution at nucleotide position 3824. The arginine at codon 1275 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.
Fulgent Genetics, Fulgent Genetics	RCV001094184	SCV002779542	uncertain significance	Charcot-Marie-Tooth disease type 4B2	2022-03-08	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000215903	SCV004225368	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000215903	SCV005191164	uncertain significance	not provided		criteria provided, single submitter	not provided
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000215903	SCV005198130	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001094184	SCV005878819	uncertain significance	Charcot-Marie-Tooth disease type 4B2	2024-10-30	criteria provided, single submitter	clinical testing	The SBF2 c.3824G>A; p.Arg1275His variant (rs150028248) is reported in the literature in several individuals affected with Charcot-Marie-Tooth disease, although it was not demonstrated to be disease-causing (Volodarsky 2021). This variant is found in the general population with an overall allele frequency of 0.046% (131/282,650 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.632). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792.