Submissions for variant NM_003571.4(BFSP2):c.1115C>T (p.Ala372Val)

gnomAD frequency: 0.00025  dbSNP: rs139944598

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000818039	SCV000958631	uncertain significance	Cataract 12 multiple types	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 372 of the BFSP2 protein (p.Ala372Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs139944598, ExAC 0.05%). This variant has not been reported in the literature in individuals affected with BFSP2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Illumina Laboratory Services, Illumina	RCV000818039	SCV001311008	benign	Cataract 12 multiple types	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV002537429	SCV003686284	uncertain significance	Inborn genetic diseases	2021-07-09	criteria provided, single submitter	clinical testing	The c.1115C>T (p.A372V) alteration is located in exon 6 (coding exon 6) of the BFSP2 gene. This alteration results from a C to T substitution at nucleotide position 1115, causing the alanine (A) at amino acid position 372 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000818039	SCV001552601	uncertain significance	Cataract 12 multiple types		no assertion criteria provided	clinical testing	The BFSP2 p.A372V variant was not identified in the literature but was identified in dbSNP (ID: rs139944598) and ClinVar (classified as uncertain significance by Invitae for cataract 12, multiple types and benign by Illumina for cataract 12, multiple types). The variant was identified in control databases in 81 of 281552 chromosomes at a frequency of 0.0002877, and was observed at the highest frequency in the European (non-Finnish) population in 72 of 128374 chromosomes (freq: 0.0005609) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.A372 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001726338	SCV001963225	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001726338	SCV001969978	uncertain significance	not provided		no assertion criteria provided	clinical testing