Submissions for variant NM_005343.4(HRAS):c.398T>A (p.Leu133His)

gnomAD frequency: 0.00001  dbSNP: rs766801436

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456787	SCV000550349	uncertain significance	Costello syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 133 of the HRAS protein (p.Leu133His). This variant is present in population databases (rs766801436, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 409951). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000681068	SCV000808522	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Has not been previously published as pathogenic or benign to our knowledge
AiLife Diagnostics, AiLife Diagnostics	RCV000681068	SCV002503211	uncertain significance	not provided	2021-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002374788	SCV002625574	uncertain significance	Cardiovascular phenotype	2022-04-06	criteria provided, single submitter	clinical testing	The p.L133H variant (also known as c.398T>A), located in coding exon 3 of the HRAS gene, results from a T to A substitution at nucleotide position 398. The leucine at codon 133 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV001535653	SCV001749703	not provided	Linear nevus sebaceous syndrome; Costello syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-18-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genetic Services Laboratory, University of Chicago	RCV003151066	SCV003839597	uncertain significance	not specified	2022-08-01	no assertion criteria provided	clinical testing	DNA sequence analysis of the HRAS gene demonstrated a sequence change, c.398T>A, in exon 4 that results in an amino acid change, p.Leu133His. This sequence change does not appear to have been previously described in individuals with HRAS-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.0008% (dbSNP rs766801436). The p.Leu133His change affects a highly conserved amino acid residue located in a domain of the HRAS protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu133His substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu133His change remains unknown at this time.