NM_005343.4:c.35G>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_005343.4(HRAS):c.35G>T(p.Gly12Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Consequence

HRAS
NM_005343.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.82

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 3) in uniprot entity RASH_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_005343.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 11-534288-C-A is Pathogenic according to our data. Variant chr11-534288-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4 link	c.35G>T	p.Gly12Val	missense_variant	Exon 2 of 6	ENST00000311189.8	NP_005334.1	P01112-1X5D945
HRAS	NM_176795.5 link	c.35G>T	p.Gly12Val	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.35G>T	p.Gly12Val	missense_variant	Exon 2 of 6	1	NM_005343.4	ENSP00000309845.7		P01112-1
HRAS	ENST00000417302.7 link	c.35G>T	p.Gly12Val	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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Costello syndrome

Pathogenic:6

Apr 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 07, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2014

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly12Val variant in HRAS has been reported in the literature in a proband wi th Costello syndrome and was verified to have occured de novo in that individual (Aoki 2005). While the reported proband had an alternate DNA change (c.35_36del insTT), the predicted protein change is identical to that predicted for this pat ient. This Gly12Val variant is commonly seen as a somatic mutation in several ca ncers (Catalogue of Somatic Mutations in Cancer, http://www.sanger.ac.uk/cosmic) and functional studies have shown it to dramatically alter cell growth (Aoki 20 05). Therefore, this variant is highly likely to be pathogenic. -

Aug 29, 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 valine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12600). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 24224811). 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, 20979192, 21834037, 21850009, 22317973, 23751039). 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. -

Epidermal nevus

Pathogenic:1

Apr 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Malignant tumor of urinary bladder

Pathogenic:1

Apr 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Jun 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a slower activation rate and reduced catalytic activity (PMID: 23487764, 24224811); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34184824, 24224811, 22584058, 24057668, 23376849, 23093928, 22495892, 24803665, 27195699, 26325505, 28455154, 17412879, 30664540, 31974414, 29493581, 23487764) -

Cardiovascular phenotype

Pathogenic:1

Jul 25, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35G>T (p.G12V) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to T substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed or determined to be the result of a de novo mutation in multiple individuals with features consistent with HRAS-related RASopathy (Aoki, 2005; van der Burgt, 2007; Burkitt-Wright, 2012). Another alteration at the same codon, c.34G>A (p.G12S), was reported in multiple individuals with features consistent with HRAS-related RASopathy (Aoki, 2005). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Myopathy, congenital, with excess of muscle spindles

Pathogenic:1

Apr 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HRAS-related disorder

Pathogenic:1

Aug 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HRAS c.35G>T variant is predicted to result in the amino acid substitution p.Gly12Val. This variant has been reported as a recurrent de novo variant in multiple individuals with Costello syndrome (Patient 4, Burkitt-Wright et al 2012. PubMed ID: 22495892; van der Burgt et al 2007. PubMed ID: 17412879; Bend et al. 2019. PubMed ID: 30664540; Vora et al. 2020. PubMed ID: 31974414). Of note, >90% of pathogenic HRAS variants alter the conserved glycine residues at positions 12 and 13 (Aoki et al. 2005. PubMed ID: 16170316; Gripp et al. 2006. PubMed ID: 16329078; van der Burgt et al 2007. PubMed ID: 17412879). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

.;D;.;D;D

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.4

M;M;M;M;M

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.2

D;D;D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

0.69

P;P;P;P;P

Vest4

0.84

MutPred

0.92

Loss of ubiquitination at K16 (P = 0.1037);Loss of ubiquitination at K16 (P = 0.1037);Loss of ubiquitination at K16 (P = 0.1037);Loss of ubiquitination at K16 (P = 0.1037);Loss of ubiquitination at K16 (P = 0.1037);

MVP

0.96

MPC

2.0

ClinPred

1.0

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.97

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