Submissions for variant NM_030962.4(SBF2):c.1424A>G (p.Gln475Arg)

gnomAD frequency: 0.00056  dbSNP: rs199894823

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206478	SCV000260833	uncertain significance	Charcot-Marie-Tooth disease type 4	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 475 of the SBF2 protein (p.Gln475Arg). This variant is present in population databases (rs199894823, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792, 34169998). ClinVar contains an entry for this variant (Variation ID: 220352). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SBF2 protein function with a negative 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.
Illumina Laboratory Services, Illumina	RCV001094223	SCV000375075	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.
GeneDx	RCV000413369	SCV000492176	uncertain significance	not provided	2016-11-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SBF2 gene. The Q475R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The Q475R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Athena Diagnostics	RCV000413369	SCV001145361	uncertain significance	not provided	2019-05-10	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172793	SCV001335862	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390547	SCV002698414	uncertain significance	Inborn genetic diseases	2023-12-21	criteria provided, single submitter	clinical testing	The c.1424A>G (p.Q475R) alteration is located in exon 14 (coding exon 14) of the SBF2 gene. This alteration results from a A to G substitution at nucleotide position 1424, causing the glutamine (Q) at amino acid position 475 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001094223	SCV005875780	uncertain significance	Charcot-Marie-Tooth disease type 4B2	2024-09-13	criteria provided, single submitter	clinical testing	The SBF2 c.1424A>G; p.Gln475Arg variant (rs199894823, ClinVar Variation ID: 220352) is reported rarely in individuals with Charcot-Marie-Tooth disease (Volodarsky 2021, Yalcintepe 2021). This variant is found in the general population with an overall allele frequency of 0.03% (90/282862 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.705). 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. PMID: 32376792. Yalcintepe S et al. The Importance of Multiple Gene Analysis for Diagnosis and Differential Diagnosis in Charcot Marie Tooth Disease. Turk Neurosurg. 2021 PMID: 34169998.