Submissions for variant NM_002524.5(NRAS):c.225C>T (p.Gly75=)

gnomAD frequency: 0.00123  dbSNP: rs142739534

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154799	SCV000204479	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Gly75Gly in Exon 03 of NRAS: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence. It has been identified in 0.3% (10/3738) of Afri can American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs142739534).
GeneDx	RCV000157673	SCV000208915	benign	not provided	2018-08-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000320449	SCV000347396	likely benign	Noonan syndrome 6	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV001086742	SCV000563314	benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154799	SCV000697987	benign	not specified	2020-08-03	criteria provided, single submitter	clinical testing	Variant summary: NRAS c.225C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0003 in 251478 control chromosomes, predominantly at a frequency of 0.0039 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1560 fold of 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 a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.225C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four other ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=3) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002444638	SCV002737830	benign	Cardiovascular phenotype	2020-03-24	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003952766	SCV004772128	likely benign	NRAS-related disorder	2019-07-15	criteria provided, single submitter	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).
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157673	SCV000207644	uncertain significance	not provided	2015-01-15	no assertion criteria provided	clinical testing