ClinVar Miner

Submissions for variant NM_000143.4(FH):c.4T>C (p.Tyr2His)

gnomAD frequency: 0.00023  dbSNP: rs112335468
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001662540 SCV000632463 likely benign not provided 2024-01-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023401 SCV001185270 likely benign Hereditary cancer-predisposing syndrome 2024-01-23 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.
GeneDx RCV001662540 SCV001874034 uncertain significance not provided 2024-07-09 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with pheochromocytoma, paraganglioma, kidney cancer, or colon cancer (PMID: 29684080, 30877234); This variant is associated with the following publications: (PMID: 30877234, 29684080, 37529773)
Sema4, Sema4 RCV001023401 SCV002535560 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-24 criteria provided, single submitter curation
Baylor Genetics RCV003459206 SCV004197337 uncertain significance Fumarase deficiency 2024-03-04 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004555584 SCV004783271 uncertain significance FH-related disorder 2023-10-30 no assertion criteria provided clinical testing The FH c.4T>C variant is predicted to result in the amino acid substitution p.Tyr2His. This variant has been reported in one individual with pheochromocytoma as a germline variant of unknown significance (Supplementary Table S3 in Ben Aim et al. 2019. PubMed ID: 30877234). This variant is reported in 0.070% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-241683019-A-G). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/460359/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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