Submissions for variant NM_001003800.2(BICD2):c.2234C>T (p.Ser745Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581545	SCV004369541	uncertain significance	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	2023-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 745 of the BICD2 protein (p.Ser745Leu). 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. 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 expected to disrupt BICD2 protein function. This variant has not been reported in the literature in individuals affected with BICD2-related conditions. This variant is present in population databases (rs781440350, gnomAD 0.0009%).
Molecular Genetics, Royal Melbourne Hospital	RCV003581545	SCV004812481	uncertain significance	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	2022-06-02	criteria provided, single submitter	clinical testing	This sequence change in BICD2 is predicted to replace serine with leucine at codon 745, p.(Ser745Leu). The serine residue is highly conserved (100 vertebrates, UCSC), and is located in the coiled-coil 3 domain in a region (amino acids 734-747) that is defined as a mutational hotspot (PMID: 32057122). There is a large physicochemical difference between serine and leucine. This variant is absent from gnomAD v3.1. To our knowledge, this variant has not been reported in the literature in any individuals with BICD2-related disease. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, PM2_Supporting, PP3.
Ambry Genetics	RCV004604977	SCV005098682	uncertain significance	Inborn genetic diseases	2024-04-15	criteria provided, single submitter	clinical testing	The c.2234C>T (p.S745L) alteration is located in exon 6 (coding exon 6) of the BICD2 gene. This alteration results from a C to T substitution at nucleotide position 2234, causing the serine (S) at amino acid position 745 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.