Submissions for variant NM_001122955.4(BSCL2):c.299G>T (p.Cys100Phe)

gnomAD frequency: 0.00023  dbSNP: rs147314661

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235352	SCV000294094	uncertain significance	not provided	2025-03-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18790819)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543721	SCV000657771	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 36 of the BSCL2 protein (p.Cys36Phe). This variant is present in population databases (rs147314661, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BSCL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 246509). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BSCL2 protein function with a negative predictive value of 80%. 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	RCV002418047	SCV002726376	uncertain significance	Inborn genetic diseases	2021-04-27	criteria provided, single submitter	clinical testing	The c.107G>T (p.C36F) alteration is located in exon 2 (coding exon 1) of the BSCL2 gene. This alteration results from a G to T substitution at nucleotide position 107, causing the cysteine (C) at amino acid position 36 to be replaced by a phenylalanine (F). The heterozygous missense change is ultra rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the BSCL2 c.107G>T alteration was observed in <0.001% (2/277,084). A similar amino acid change has been observed in an affected individual: _x000D_ _x000D_ A similar missense change affecting the same amino acid c.107G>A (p.C36Y) was reported in a patient with spastic paraplegia mild mental retardation, and no amyotrophy (Ishiura, 2014). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.C36 amino acid is highly conserved in available vertebrate species. In silico prediction is conflicting:_x000D_ _x000D_ The p.C36F alteration is predicted to be possibly damaging by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002479947	SCV002784480	likely benign	Congenital generalized lipodystrophy type 2; Hereditary spastic paraplegia 17; Severe neurodegenerative syndrome with lipodystrophy; Neuronopathy, distal hereditary motor, type 5C	2024-02-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930012	SCV004743076	uncertain significance	BSCL2-related disorder	2023-12-06	no assertion criteria provided	clinical testing	The BSCL2 c.299G>T variant is predicted to result in the amino acid substitution p.Cys100Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.