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

dbSNP: rs766909143

Total submissions: 6

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000872282	SCV001014074	likely benign	Costello syndrome	2024-11-04	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
PreventionGenetics, part of Exact Sciences	RCV003962443	SCV004786014	likely benign	HRAS-related disorder	2023-09-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).