ClinVar Miner

Submissions for variant NM_004960.4(FUS):c.1292C>T (p.Pro431Leu)

gnomAD frequency: 0.00016  dbSNP: rs186547381
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000711709 SCV000842096 uncertain significance not provided 2017-10-09 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000765290 SCV000896545 uncertain significance Amyotrophic lateral sclerosis type 6; Tremor, hereditary essential, 4 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000765290 SCV002259005 uncertain significance Amyotrophic lateral sclerosis type 6; Tremor, hereditary essential, 4 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 431 of the FUS protein (p.Pro431Leu). This variant is present in population databases (rs186547381, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of FUS-related conditions (PMID: 22863194, 25382069, 25558820, 28430856, 30279455, 32638105). ClinVar contains an entry for this variant (Variation ID: 37069). 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 tolerated. 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 RCV002381274 SCV002692835 likely benign Inborn genetic diseases 2019-12-28 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Genetics, Royal Melbourne Hospital RCV003993752 SCV004812574 uncertain significance Amyotrophic lateral sclerosis 2024-03-01 criteria provided, single submitter clinical testing This sequence change in FUS is predicted to replace proline with leucine at codon 431, p.(Pro431Leu). The proline residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the RANBP2-type zinc finger domain in a region (amino acids 429-438) that is highly intolerant to missense variation. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.06% (38/60,008 alleles) in the Admixed American population. This variant has been reported in individuals with Alzheimer disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease, and unaffected individuals (PMID: 20138404, 22863194, 25382069, 25558820, 28430856, 29486463, 30279455, 32638105). Computational evidence is uninformative for the missense substitution (REVEL = 0.522). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1.
Breakthrough Genomics, Breakthrough Genomics RCV000711709 SCV005194333 uncertain significance not provided criteria provided, single submitter not provided
OMIM RCV000030718 SCV000053379 pathogenic Tremor, hereditary essential, 4 2012-08-10 no assertion criteria provided literature only
Guerreiro-Bras Laboratory, Van Andel Institute RCV001847624 SCV002106327 likely pathogenic Frontotemporal dementia 2022-02-02 no assertion criteria provided research
PreventionGenetics, part of Exact Sciences RCV003407373 SCV004115158 uncertain significance FUS-related disorder 2024-01-05 no assertion criteria provided clinical testing The FUS c.1292C>T variant is predicted to result in the amino acid substitution p.Pro431Leu. This variant was reported in an individual with essential tremor, an individual with Parkinson Disease, and a few cases of amyotrophic lateral sclerosis (Merner et al. 2012. PubMed ID: 22863194; Cady et al. 2014. PubMed ID: 25382069; Steele et al. 2015. PubMed ID: 25558820; Morgan et al. 2017. PubMed ID: 28430856; Gromicho et al. 2020. PubMed ID: 32638105). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.