Submissions for variant NM_001003800.2(BICD2):c.2240G>T (p.Arg747Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002848348	SCV003234926	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	2023-04-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 747 of the BICD2 protein (p.Arg747Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BICD2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 2030246). 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 disrupts the p.Arg747 amino acid residue in BICD2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24336790; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV002848348	SCV004810291	uncertain significance	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	2024-04-04	criteria provided, single submitter	clinical testing