11-534288-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. 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 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.82

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]

ACMG classification

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, 0.983
• PP5: Variant 11-534288-C-T is Pathogenic according to our data. Variant chr11-534288-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534288-C-T is described in UniProt as null. Variant chr11-534288-C-T is described in UniProt as null. Variant chr11-534288-C-T is described in UniProt as null. Variant chr11-534288-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.35G>A	p.Gly12Asp	missense_variant	Exon 2 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.35G>A	p.Gly12Asp	missense_variant	Exon 2 of 6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.35G>A	p.Gly12Asp	missense_variant	Exon 2 of 6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.35G>A	p.Gly12Asp	missense_variant	Exon 2 of 6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:5

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. -

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. -

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. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PM6_Supporting+PP4+PP3_Moderate+PM5_Strong -

not provided Pathogenic:2

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) -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

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;.;D;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;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.46	P;P;P;P;P
Vest4		0.79
MutPred		0.96		Loss of catalytic residue at G10 (P = 0.0752);Loss of catalytic residue at G10 (P = 0.0752);Loss of catalytic residue at G10 (P = 0.0752);Loss of catalytic residue at G10 (P = 0.0752);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

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

Publications

LitVar

Other links and lift over

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