ClinVar Miner

Submissions for variant NM_005022.4(PFN1):c.350A>G (p.Glu117Gly)

gnomAD frequency: 0.00060  dbSNP: rs140547520
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV002247400 SCV002518469 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002247400 SCV003922948 uncertain significance not specified 2023-03-06 criteria provided, single submitter clinical testing Variant summary: PFN1 c.350A>G (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 0.0005 in 251482 control chromosomes. This frequency does not allow conclusions about variant significance. c.350A>G has been reported in the literature in individuals affected with PFN1-Related Disorders such as familial and sporadic Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD) and in unaffected controls with a reported moderate risk of association and a 95% CI that slightly overlaps 1 (example, PMID: 24309268). These report(s) do not provide unequivocal conclusions about an inherited penetrant association of the variant with PFN1-Related Disorders. Experimental evidence demonstrating an impact on protein function have suggested conflicting mechanism of action, namely gain of function due to TDP43 accumulation and loss of function due to altered stress granule dynamics (example, PMID: 26908597). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen RCV005243103 SCV005892732 benign not provided 2025-02-01 criteria provided, single submitter clinical testing PFN1: BS1, BS2
OMIM RCV000030697 SCV000053358 pathogenic Amyotrophic lateral sclerosis type 18 2012-08-23 no assertion criteria provided literature only

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