rs104894229

chr11-534289-C-Achr11-534289-C-Gchr11-534289-C-T

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.34G>T(p.Gly12Cys) variant causes a missense 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 (★★). 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 criteria provided, multiple submitters, no conflicts P:39
• Conservation: PhyloP100: 6.09

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:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 3) in uniprot entity RASH_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) 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 id is 12602.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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/exons	MANE	UniProt
HRAS	NM_005343.4	c.34G>T	p.Gly12Cys	missense_variant	2/6	ENST00000311189.8
HRAS	NM_176795.5	c.34G>T	p.Gly12Cys	missense_variant	2/6	ENST00000417302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRAS	ENST00000311189.8	c.34G>T	p.Gly12Cys	missense_variant	2/6	1	NM_005343.4	P1
HRAS	ENST00000417302.7	c.34G>T	p.Gly12Cys	missense_variant	2/6	5	NM_176795.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:39

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jun 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Sep 21, 2022	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 07, 2022	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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 20, 2012	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2020	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	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. -

Myelodysplastic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Multiple myeloma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Epidermal nevus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 2012

- -

Nasopharyngeal neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Adenoid cystic carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Papillary renal cell carcinoma, sporadic Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Nevus sebaceous Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 2012

- -

Ovarian serous cystadenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Urinary bladder carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Uterine carcinosarcoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pancreatic adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of uterine cervix Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Thyroid tumor Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

RASopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Baylor Genetics

-

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	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.1	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
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	D
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

Other links and lift over

dbSNP: rs104894229; hg19: chr11-534289; COSMIC: COSV54236828; COSMIC: COSV54236828;