ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.291-6T>G

dbSNP: rs766909143
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000521008 SCV000616473 benign RASopathy 2017-04-18 reviewed by expert panel curation The filtering allele frequency of the c.291-6T>G variant in the HRAS gene is 0.051% (14/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
Invitae RCV000872282 SCV001014074 likely benign Costello syndrome 2024-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255585 SCV001432087 benign not specified 2020-08-10 criteria provided, single submitter clinical testing Variant summary: HRAS c.291-6T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251312 control chromosomes, predominantly at a frequency of 0.00098 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 196 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 a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.291-6T>G in individuals affected with Costello Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign (ClinGen RASopathy Variant Curation Expert Panel) and likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4 RCV002257777 SCV002537975 likely benign Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002497006 SCV002805666 likely benign Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2 2021-10-21 criteria provided, single submitter clinical testing

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