11-534288-C-G

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>C(p.Gly12Ala) 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:10

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:

Genome browser will be placed here

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, 0.98

PP5

Variant 11-534288-C-G is Pathogenic according to our data. Variant chr11-534288-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 12603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534288-C-G is described in UniProt as null. Variant chr11-534288-C-G is described in UniProt as null. Variant chr11-534288-C-G is described in UniProt as null. Variant chr11-534288-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4 link	c.35G>C	p.Gly12Ala	missense_variant	Exon 2 of 6	ENST00000311189.8	NP_005334.1	P01112-1X5D945
HRAS	NM_176795.5 link	c.35G>C	p.Gly12Ala	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>C	p.Gly12Ala	missense_variant	Exon 2 of 6	1	NM_005343.4	ENSP00000309845.7		P01112-1
HRAS	ENST00000417302.7 link	c.35G>C	p.Gly12Ala	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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Costello syndrome

Pathogenic:4

Jul 17, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The HRAS c.35G>C (p.Gly12Ala) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that this variant increased RAS pathway activation in NIH 3T3 cells (Niihori_JHG_2011) and increased proliferation in Ba/F3 cells (Denayer_HM_2008). The variant of interest has not been found in a large, broad control population, ExAC in 120014 control chromosomes. This variant was reported in multiple Costello syndrome patients, including de novo occurrences (Aoki_NatGen_2005, Robbins_AJMG_2016, Niihori_JHG_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Apr 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt HRAS function. ClinVar contains an entry for this variant (Variation ID: 12603). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Ala). -

Jul 22, 2024

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was found de novo in a child with Costello syndrome. It disrupts the p.Gly12 amino acid residue in HRAS. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). In silico prediction indicates that this missense variant is expected to disrupt HRAS function. This missense change has been observed in individuals with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Sep 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect caused by increased phosphorylation of ERK, suggesting an activation of the RAS/MAPK pathway (Denayer et al., 2008; Niihori et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17979197, 28027064, 17601930, 30055033, 34845155, 24224811, 21686750, 22317973, 23093928, 16170316, 19035362, 24803665, 27589201, 24169525, 16835863, 30762279, 30885829, 31394527, 31560489, 33482860, 33224014, 37488489, 33057194, 35982159, 34643321, 21850009) -

Jun 04, 2014

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Mar 03, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdomyosarcoma

Pathogenic:1

Sep 01, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

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:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Apr 06, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

.;D;.;D;D

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.1

M;M;M;M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.7

D;D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;D;D

Polyphen

0.83

P;P;P;P;P

Vest4

0.80

MutPred

0.94

Loss of ubiquitination at K16 (P = 0.1191);Loss of ubiquitination at K16 (P = 0.1191);Loss of ubiquitination at K16 (P = 0.1191);Loss of ubiquitination at K16 (P = 0.1191);Loss of ubiquitination at K16 (P = 0.1191);

MVP

0.93

MPC

2.1

ClinPred

0.99

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.96

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