ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.508A>T (p.Lys170Ter)

gnomAD frequency: 0.00005  dbSNP: rs372936166
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000551172 SCV000927031 uncertain significance Costello syndrome 2019-06-27 reviewed by expert panel curation The c.508A>T (p.Lys170Ter) variant in the HRAS gene has been identified in patients with cancer and individuals who underwent testing for RASopathies, however it was also identified in an unaffected parent (BS4; Invitae, GeneDx internal data, GTR Lab ID: 26957, 500031; SCV000207840.14, SCV000635092.3). The filtering allele frequency of the p.Lys170Ter variant is 0.0034% for European (non-Finnish) chromosomes by the gnomAD aggregation database (8/249358 with 95% CI), which is not a high enough frequency to meet thresholds defined by the ClinGen RASopahty Expert panel for autosomal dominant RASopathy variants (BA1/BS1 not met). Furthermore, LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore the PVS1 rule is not applicable. In summary, the clinical significance of the p.Lys170Ter variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4.
GeneDx RCV000157909 SCV000207840 likely benign not provided 2019-10-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28873162, 29625052)
Invitae RCV000551172 SCV000635092 uncertain significance Costello syndrome 2023-12-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys170*) in the HRAS gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HRAS cause disease. This variant is present in population databases (rs372936166, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 40447). 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.
Fulgent Genetics, Fulgent Genetics RCV002477044 SCV002790396 uncertain significance Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2 2021-10-30 criteria provided, single submitter clinical testing

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