ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.546G>A (p.Met182Ile)

gnomAD frequency: 0.00001  dbSNP: rs748639813
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000229010 SCV000288863 uncertain significance Costello syndrome 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 182 of the HRAS protein (p.Met182Ile). This variant is present in population databases (rs748639813, gnomAD 0.01%). 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: 240138). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function with a negative predictive value of 95%. 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.
Revvity Omics, Revvity RCV000229010 SCV003811237 uncertain significance Costello syndrome 2019-06-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003993902 SCV004814067 likely benign not specified 2024-02-19 criteria provided, single submitter clinical testing Variant summary: HRAS c.546G>A (p.Met182Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 779530 control chromosomes gnomAD database (v4.0.0). The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in HRAS causing Costello Syndrome phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.546G>A in individuals affected with Costello Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 240138). Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics, Fulgent Genetics RCV005049496 SCV005684751 uncertain significance Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2 2024-05-22 criteria provided, single submitter clinical testing

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