Submissions for variant NM_030962.4(SBF2):c.3761T>C (p.Leu1254Pro)

dbSNP: rs762211340

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094186	SCV000375047	uncertain significance	Charcot-Marie-Tooth disease type 4B2	2018-01-12	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	RCV000264501	SCV000815073	uncertain significance	Charcot-Marie-Tooth disease type 4	2020-06-08	criteria provided, single submitter	clinical testing	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. 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SBF2-related disease. ClinVar contains an entry for this variant (Variation ID: 306585). This variant is present in population databases (rs762211340, ExAC 0.05%). This sequence change replaces leucine with proline at codon 1254 of the SBF2 protein (p.Leu1254Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.
Ambry Genetics	RCV002348042	SCV002619718	uncertain significance	Inborn genetic diseases	2020-11-25	criteria provided, single submitter	clinical testing	The p.L1254P variant (also known as c.3761T>C), located in coding exon 28 of the SBF2 gene, results from a T to C substitution at nucleotide position 3761. The leucine at codon 1254 is replaced by proline, an amino acid with 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.