Submissions for variant NM_030962.4(SBF2):c.3290C>A (p.Thr1097Asn)

gnomAD frequency: 0.00054  dbSNP: rs141894081

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000416078	SCV000293367	likely benign	not provided	2020-10-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32376792)
CeGaT Center for Human Genetics Tuebingen	RCV000416078	SCV000493523	likely benign	not provided	2024-12-01	criteria provided, single submitter	clinical testing	SBF2: BP1
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085919	SCV000657953	likely benign	Charcot-Marie-Tooth disease type 4	2024-12-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001114470	SCV001272357	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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172800	SCV001335869	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001114470	SCV001440509	uncertain significance	Charcot-Marie-Tooth disease type 4B2	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Athena Diagnostics	RCV000416078	SCV001475456	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
Mayo Clinic Laboratories, Mayo Clinic	RCV000416078	SCV001716092	uncertain significance	not provided	2019-06-09	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001564019	SCV001786704	likely pathogenic	Tip-toe gait	2021-05-31	criteria provided, single submitter	clinical testing	We examined a family. The child and the mother both are toe-walkers and both have gene variant SBF2 c.3290C>A. Father is not toe-walker and he doesn't have this variant. Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Ambry Genetics	RCV002321906	SCV002606046	likely benign	Inborn genetic diseases	2021-08-17	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001114470	SCV003799442	uncertain significance	Charcot-Marie-Tooth disease type 4B2	2023-09-06	criteria provided, single submitter	clinical testing	The SBF2 c.3290C>A; p.Thr1097Asn variant (rs141894081) is reported in the literature in two individuals undergoing CMT testing (Volodarsky 2021); however, the variant was not determined to be causative. The variant is reported in the ClinVar database (Variation ID: 246062) and is listed in the Latino population with an allele frequency of 0.35% (124/35,440 alleles) in the Genome Aggregation Database. The threonine at codon 1097 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.198). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of the p.Thr1097Asn 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.
PreventionGenetics, part of Exact Sciences	RCV003919998	SCV004728552	likely benign	SBF2-related disorder	2022-02-26	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).