11-534288-C-T

Variant names:

• chr11-534288-C-T
• rs104894230
• NM_005343.4:c.35G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005343.4(HRAS):​c.35G>A​(p.Gly12Asp) 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.82
• Publications: 380 publications found

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]

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 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS1: Transcript NM_005343.4 (HRAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain 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 chr11-534289-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12602.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 11-534288-C-T is Pathogenic according to our data. Variant chr11-534288-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.35G>A	p.Gly12Asp	missense	Exon 2 of 6	NP_005334.1
	HRAS	NM_176795.5	MANE Plus Clinical	c.35G>A	p.Gly12Asp	missense	Exon 2 of 6	NP_789765.1
	HRAS	NM_001130442.3		c.35G>A	p.Gly12Asp	missense	Exon 2 of 5	NP_001123914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.35G>A	p.Gly12Asp	missense	Exon 2 of 6	ENSP00000309845.7
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.35G>A	p.Gly12Asp	missense	Exon 2 of 6	ENSP00000388246.1
	HRAS	ENST00000493230.5	TSL:1	n.35G>A		non_coding_transcript_exon	Exon 2 of 7	ENSP00000434023.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:6

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been observed in at least ten Costello syndrome patients, in some of whom de novo inheritance was reported (PMID: 22926243, 26916728, 27102959; ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Mar 09, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly12Asp variant in HRAS has been reported in the literature in four individ uals with severe neonatal Costello syndrome (Lo 2008, Kuniba 2009, Sinico 2010). This variant has been reported to have occurred de novo in two probands (Lo 200 8, Sinico 2010). This variant has been observed as a somatic change in tumor tis sue. Several other variants in codon 12 of HRAS are commonly observed in Costell o syndrome patients (Lin 2011). Therefore, it is highly likely that this variant is pathogenic.

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (SCV000207860, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change (p.Gly12Val, p.Gly12Ala, p.Gly12Glu, p.Gly12Cys) at the same codon has been reported as pathogenic (ClinVar ID: VCV000012600.3, VCV000040430.1, VCV000163690.1, VCV000012613.12, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.781, 3Cnet: 0.996, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Jun 09, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with aspartic acid at codon 12 of the HRAS protein (p.Gly12Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with Costello syndrome (PMID: 26916728, 18642361, 21850009, 27102959, 18039947, 22926243). In several individuals the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 12612). This variant has been reported to affect HRAS protein function (PMID: 24224811, 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, 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.

Jun 12, 2025

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2_VeryStrong, PS3_Moderate, PS4, PM1, PM2_Supporting, PM5, PP3

not provided Pathogenic:2

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies show p.(G12D) results in increased levels of the active, GTP-bound HRAS protein (PMID: 21850009); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 18642361, 35050212, 24224811, 23093928, 18039947, 22926243, 24803665, 26916728, 21344638, 17979197, 20658932, 32304219, 33502061, 33932139, 33726816, 35584285, 34958143, 21850009, 29493581)

RASopathy Pathogenic:2

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines

Oct 30, 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>A (p.Gly12Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 276492 control chromosomes. It has been reported in many CS cases and most of them with severe clinical presentations. Functional assays showed the variant to have increased activity (Niihori_2011). Variants involving codon 12 (such as p.G12S, p.G12A, p.G12C, p.G12D) have been reported in numerous affected individuals indicating it is mutation hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

COSTELLO SYNDROME, SEVERE Pathogenic:1

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nevus sebaceous Pathogenic:1

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Non-immune hydrops fetalis Pathogenic:1

Apr 30, 2020

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lip and oral cavity carcinoma Pathogenic:1

Apr 30, 2019

Institute of Medical Sciences, Banaras Hindu University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

HRAS-related disorder Pathogenic:1

Aug 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HRAS c.35G>A variant is predicted to result in the amino acid substitution p.Gly12Asp. This is a recurrent de novo variant reported in individuals with autosomal dominant Costello syndrome (Table 1, Case 5, Becher et al. 2020. PubMed ID: 32304219; Table S1, Individual ID 47, Gabriel et al. 2022. PubMed ID: 34958143; Table 2, Individual ID 28, Pezzoli et al. 2021. PubMed ID: 35050212 ). In vitro experimental studies suggest this variant impacts protein function (Niihori et al. 2011. PubMed ID: 21850009). This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic and likely pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/12612/). Alternate nucleotide changes affecting the same amino acid (p.Gly12Ala, p.Gly12Cys, and p.Gly12Ser) have been reported to be associated with Costello syndrome (Table 1, Niihori et al. 2011. PubMed ID: 21850009; ClinVar Variation IDs: 12603, 12606, and 376323). This variant is interpreted as pathogenic.

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Jul 06, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.46	P
Vest4		0.79
MutPred		0.96		Loss of catalytic residue at G10 (P = 0.0752)
MVP		0.94
MPC		1.9
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs104894230; hg19: chr11-534288; COSMIC: COSV54236774; COSMIC: COSV54236774;