ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.378A>G (p.Glu126=)

gnomAD frequency: 0.00001  dbSNP: rs397517140
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000519017 SCV000616469 benign RASopathy 2017-04-18 reviewed by expert panel curation The filtering allele frequency of the c.378A>G (p.Glu126=) variant in the HRAS gene is 0.095% (23/16510) 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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000038462 SCV000062139 likely benign not specified 2010-01-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588072 SCV000698558 benign not provided 2016-10-03 criteria provided, single submitter clinical testing Variant summary: The HRAS c.378A>G (p.Glu126Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 1/5 splice prediction tools predict that this variant may create a novel 3' splicing acceptor site. 2/5 splice prediction tools predict that this variant may weaken a cryptic 3' splicing acceptor site. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 25/120908 control chromosomes at a frequency of 0.0002068, which is approximately 83 times the estimated maximal expected allele frequency of a pathogenic HRAS variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV001081660 SCV000758760 benign Costello syndrome 2024-01-08 criteria provided, single submitter clinical testing
GeneDx RCV000588072 SCV001942936 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813237 SCV002060516 benign Noonan syndrome and Noonan-related syndrome 2020-09-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV002345262 SCV002623301 benign Cardiovascular phenotype 2021-05-18 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.

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