Submissions for variant NM_005022.4(PFN1):c.350_351delinsGT (p.Glu117Gly)

dbSNP: rs1597686012

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800637	SCV000940366	uncertain significance	not provided	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 117 of the PFN1 protein (p.Glu117Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD) (PMID: 22801503, 23063648, 23141414, 23312802, 23634771, 23635659, 24309268, 25943890). ClinVar contains an entry for this variant (Variation ID: 646360). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PFN1 function (PMID: 22801503, 24920614, 26056300, 27432186, 28040732, 35628504). 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.
Athena Diagnostics	RCV000800637	SCV001144913	uncertain significance	not provided	2019-07-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000800637	SCV001950522	benign	not provided	2020-09-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22801503, 25943890, 23634771, 23063648, 26226631, 25499087, 23312802, 23141414)
Genetic Services Laboratory, University of Chicago	RCV001815012	SCV002061924	uncertain significance	not specified	2020-03-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001815012	SCV003922949	uncertain significance	not specified	2023-03-10	criteria provided, single submitter	clinical testing	Variant summary: PFN1 c.350_351delinsGT (p.Glu117Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 282822 control chromosomes (gnomAD). This frequency does not allow any conclusion about variant significance. c.350_351delinsGT has been reported in the literature in individuals affected with PFN1-Related Disorders (example: Wu_2012, Tiloca_2013, Ingre_2013, Dillen_2013, vanBlitterswijk_2013, Yang_2013, Pottier_2015, Fratta_2013, and Smith_2015) as well as study control subjects (example: Wu_2012, Dillen_2013, van Blitterswijk_2013, Fratta_2013, Smith_2015). In at-least, one of these individuals a pathogenic co-occurrence on GRN (p.A303GfsX14) was reported (Dillen_2013). Multiple reports have provided experimental evidence evaluating an impact on protein function. While some studies showed no damaging effect of this variant (example: Wu_2012, and Figley_ 2014) few others suggest this variant could be a risk factor for disease (example: Boopathy_2014 and Tanaka_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after and classified the variant as VUS (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.