rs104894229

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001318054.2(HRAS):c.-286G>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 34)

Consequence

HRAS
NM_001318054.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 6.09

Variant links:

Genes affected

HRAS (HGNC:5173): (HRas proto-oncogene, GTPase) This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]

HRAS links:

LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]

LRRC56 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 11-534289-C-A is Pathogenic according to our data. Variant chr11-534289-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534289-C-A is described in UniProt as null. Variant chr11-534289-C-A is described in UniProt as null. Variant chr11-534289-C-A is described in UniProt as null. Variant chr11-534289-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4 link	c.34G>T	p.Gly12Cys	missense_variant	Exon 2 of 6	ENST00000311189.8	NP_005334.1	P01112-1X5D945
HRAS	NM_176795.5 link	c.34G>T	p.Gly12Cys	missense_variant	Exon 2 of 6	ENST00000417302.7	NP_789765.1	P01112-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8 link	c.34G>T	p.Gly12Cys	missense_variant	Exon 2 of 6	1	NM_005343.4	ENSP00000309845.7		P01112-1
HRAS	ENST00000417302.7 link	c.34G>T	p.Gly12Cys	missense_variant	Exon 2 of 6	5	NM_176795.5	ENSP00000388246.1		P01112-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Costello syndrome

Pathogenic:7

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the HRAS protein (p.Gly12Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Costello syndrome (PMID: 16443854, 18039947, 22926243). ClinVar contains an entry for this variant (Variation ID: 12613). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 04, 2014

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HRAS c.34G>T (p.Gly12Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250294 control chromosomes (gnomAD). c.34G>T has been reported in the literature in multiple individuals affected with Costello Syndrome (e.g. Niihori_2011, McCormick_2013, Choi_2019). These data indicate that the variant is very likely to be associated with disease. In functional studies, Niihori et al (Niihori_2011) report that there was an increase in guanosine triphosphate (GTP)-bound HRAS and activation of RAS signaling pathway (as measured by the activation of ELK1 and c-Jun) in cells transfected with the variant of interest. In addition, HGMD database reports several other missense variants affecting the same codon and nearby codons (e.g. p.G12R, p.G12S, p.G12V, p.G12A, p.G13D, p.G13C) suggesting this area might be a mutational hotspot. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 20, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly12Cys variant in HRAS has been reported in the literature in six individu als with severe neonatal Costello syndrome (Kerr 2006, Lo 2008, Lin 2009, Niihor i 2011, Lorenz 2012). This variant has been reported to have occurred de novo in one proband (Lorenz 2012). Several other DNA variants affecting codon 12 of HRA S are commonly observed in patients with Costello syndrome (Niihori 2011). There fore, this variant is highly likely to be pathogenic. -

Sep 21, 2022

Breda Genetics srl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant in c.34G>T (p.Gly12Cys) in HRAS gene is reported as pathogenic for Costello syndrome and other HRAS-related diseases in ClinVar (Variation ID: 12613) and in the Global Variome shared LOVD database v.3.0 (genomic variant: #0000345686). There is no information on frequency in gnomAD or 1000 Genomes Project. The variant has been reported in in multiple individuals affected with Costello Syndrome (Choi et al., 2019, PMID: 31394527; McCormick et al., 2013, PMID: 23429430; Niihori et al., 2011, PMID: 21850009). -

Jul 09, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria:PP3, PP5, PM2_P, PM1, PM5, PS3; Variant was found in heterozygous state -

not provided

Pathogenic:4

Oct 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HRAS c.34G>T; p.Gly12Cys variant (rs104894229; ClinVar Variation ID: 12613) is reported in the literature as a recurrent de novo variant in multiple individuals affected with Costello syndrome (Choi 2019, Kerr 2006, Lorenz 2012). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011). Functional characterization of the p.Gly12Cys protein indicates increased downstream MEK signaling activity (Niihori 2011), consistent with the established disease mechanism of Costello syndrome. Based on available information, this variant is considered to be pathogenic. References: Choi N et al. Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome. Cytogenet Genome Res. 2019;158(4):184-191. PMID: 31394527. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006 May;43(5):401-5. PMID: 16443854 Lorenz S et al Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D. Eur J Med Genet. 2012 Nov;55(11):615-9. PMID: 22926243. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011 Oct;56(10):707-15. PMID: 21850009. -

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies of the G12C variant have shown that it results in increased active, GTP-bound HRAS (Niihori et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 16443854, 24224811, 23093928, 24803665, 31394527, 22926243, 21850009, 16155195, 18039947, 33258288, 29493581) -

Aug 14, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome

Pathogenic:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP4+PS2_Moderate+PP3+PM5 -

Nevus sebaceous

Pathogenic:1

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Epidermal nevus

Pathogenic:1

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

RASopathy

Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D;.;D;D

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.1

M;M;M;M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.2

D;D;D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0090

D;D;D;D;D

Sift4G

Uncertain

0.024

D;D;D;D;D

Polyphen

0.68

P;P;P;P;P

Vest4

0.83

MutPred

0.94

Loss of disorder (P = 0.1073);Loss of disorder (P = 0.1073);Loss of disorder (P = 0.1073);Loss of disorder (P = 0.1073);Loss of disorder (P = 0.1073);

MVP

0.97

MPC

1.8

ClinPred

1.0

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over