ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.437C>T (p.Ala146Val)

dbSNP: rs121917759
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000013445 SCV000205996 likely pathogenic Costello syndrome 2013-12-26 criteria provided, single submitter clinical testing The Ala146Val variant in HRAS has been reported in one individual with mild clin ical features of Costello syndrome (Gripp 2008), and was absent in large populat ion studies. In addition, another variant at the Ala146 residue (Ala146Thr) has also been identified as occurring de novo in one individual with mild clinical f eatures of Costello syndrome (Zampino 2007). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, MAPP, PolyPhen2, and SIFT) sugg est that this variant may impact the protein, though this information is not pre dictive enough to determine pathogenicity. In summary, this variant is likely pa thogenic, though additional studies are required to fully establish its clinical significance.
Invitae RCV000013445 SCV000826359 likely pathogenic Costello syndrome 2018-04-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 146 of the HRAS protein (p.Ala146Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with attenuated Costello syndrome (PMID: 18247425). ClinVar contains an entry for this variant (Variation ID: 12611). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The p.Ala146 amino acid residue in HRAS has been determined to be clinically significant (PMID: 17054105, 28328122). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000013445 SCV000033692 pathogenic Costello syndrome 2008-03-15 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444744 SCV000506628 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427529 SCV000506629 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436710 SCV000506630 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419902 SCV000506631 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426668 SCV000506632 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436017 SCV000506633 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only

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