Submissions for variant NM_030962.4(SBF2):c.4563A>T (p.Leu1521Phe)

gnomAD frequency: 0.00005  dbSNP: rs148988271

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489426	SCV000576993	uncertain significance	not provided	2017-04-13	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SBF2 gene. The L1521F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L1521F variant is observed in 7/66,662 (0.01%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the L1521F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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.
Illumina Laboratory Services, Illumina	RCV001111097	SCV001268606	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001321657	SCV001512495	uncertain significance	Charcot-Marie-Tooth disease type 4	2022-05-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1521 of the SBF2 protein (p.Leu1521Phe). This variant is present in population databases (rs148988271, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SBF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 426528). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002341156	SCV002637283	uncertain significance	Inborn genetic diseases	2020-12-20	criteria provided, single submitter	clinical testing	The p.L1521F variant (also known as c.4563A>T), located in coding exon 33 of the SBF2 gene, results from an A to T substitution at nucleotide position 4563. The leucine at codon 1521 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well 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.