ClinVar Miner

Submissions for variant NM_016169.4(SUFU):c.1379A>G (p.Lys460Arg)

gnomAD frequency: 0.00001  dbSNP: rs778125780
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000545540 SCV000623109 uncertain significance Gorlin syndrome; Medulloblastoma 2025-01-15 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 460 of the SUFU protein (p.Lys460Arg). This variant is present in population databases (rs778125780, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SUFU-related conditions. ClinVar contains an entry for this variant (Variation ID: 453960). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SUFU protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SUFU function (PMID: 29654263). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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 RCV000561960 SCV000675281 benign Hereditary cancer-predisposing syndrome 2023-08-29 criteria provided, single submitter clinical testing This alteration is classified as 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.
Fulgent Genetics, Fulgent Genetics RCV000763644 SCV000894515 uncertain significance Gorlin syndrome; Medulloblastoma; Familial meningioma; Joubert syndrome 32 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV001294222 SCV001483069 uncertain significance Gorlin syndrome 2018-12-17 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4 RCV000561960 SCV002527193 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-27 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001294222 SCV002584632 uncertain significance Gorlin syndrome 2022-09-09 criteria provided, single submitter clinical testing The SUFU c.1379A>G (p.Lys460Arg) missense change has a maximum subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function. Transduction of a cell line with this variant led to an increase in Hedgehog pathway activity as compared to the wild-type, suggesting that this variant may have dominant-negative activity and can interfere with function of the wild-type protein (PMID: 29654263). To our knowledge, this variant has not been reported in individuals with nevoid basal cell carcinoma syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Revvity Omics, Revvity RCV003139745 SCV003818144 uncertain significance not provided 2019-05-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV003470694 SCV004205681 uncertain significance Familial meningioma 2024-03-29 criteria provided, single submitter clinical testing

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