Submissions for variant NM_002524.5(NRAS):c.291-8G>A

gnomAD frequency: 0.00004  dbSNP: rs376187980

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037575	SCV000061233	uncertain significance	not specified	2014-05-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The 291-8G>A varian t in NRAS has been previously identified in two individuals with clinical featur es of Noonan syndrome (LMM unpublished data). However, one proband was also foun d to carry another pathogenic variant associated with Noonan syndrome, and the o ther proband's reportedly unaffected mother was also found to carry this variant (LMM unpublished data). In addition, this variant has been identified in 1/8600 European American and in 1/4406 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs376187980). This variant is located in the 3' splice region and computational tools do not sugge st an impact to splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the 291-8 G>A variant is uncertain, these data suggest that it is more likely to be benign .
Invitae	RCV000862599	SCV001003124	likely benign	RASopathy	2024-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037575	SCV001437288	benign	not specified	2020-09-08	criteria provided, single submitter	clinical testing	Variant summary: NRAS c.291-8G>A 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 6.8e-05 in 251396 control chromosomes. The observed variant frequency is approximately 27- fold the estimated maximal expected allele frequency for a pathogenic variant in NRAS causing Noonan Syndrome phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.291-8G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001707515	SCV001936294	likely benign	not provided	2021-10-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001707515	SCV004563852	likely benign	not provided	2023-01-03	criteria provided, single submitter	clinical testing