Submissions for variant NM_139343.3(BIN1):c.715G>A (p.Val239Ile)

gnomAD frequency: 0.00036  dbSNP: rs146573197

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726561	SCV000345537	uncertain significance	not provided	2016-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000726561	SCV000529984	uncertain significance	not provided	2017-12-14	criteria provided, single submitter	clinical testing	The V239I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V239I variant is observed in 63/126,240 (0.05%) alleles from individuals of European background (Lek et al., 2016). The V239I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546175	SCV000634519	uncertain significance	Myopathy, centronuclear, 2	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 239 of the BIN1 protein (p.Val239Ile). This variant is present in population databases (rs146573197, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with BIN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 290879). 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 BIN1 protein function with a positive 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.
Fulgent Genetics, Fulgent Genetics	RCV000546175	SCV000896803	uncertain significance	Myopathy, centronuclear, 2	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000546175	SCV001291616	uncertain significance	Myopathy, centronuclear, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Breda Genetics srl	RCV000546175	SCV002586264	uncertain significance	Myopathy, centronuclear, 2	2022-05-17	criteria provided, single submitter	clinical testing	The variant c.715G>A (p.Val239Ile) in the BIN1 gene is reported as uncertain in ClinVar (Variation ID: 290879) and in LOVD database v.3.0. This variant has not been reported in dbSNP, gnomAD, 1000 Genomes Project or ClinVar. There is no information on frequency in gnomAD or 1000 Genomes Project. The variant is reported with an estimated allele frequency of 0.0004 in 1000 Genomes Project, 0.0003077 in gnomAD exomes and 0.0004777 in gnomAD genomes with no homozygous individuals reported. The nucleotide position is moderately conserved across 35 mammalian species (GERP RS: 4.64). In silico analysis indicates that the variant might be damaging.
Revvity Omics, Revvity	RCV000546175	SCV003829869	uncertain significance	Myopathy, centronuclear, 2	2019-12-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000726561	SCV004224947	uncertain significance	not provided	2022-03-21	criteria provided, single submitter	clinical testing	PM2
GenomeConnect, ClinGen	RCV000546175	SCV000840285	not provided	Myopathy, centronuclear, 2		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.