rs104894230

chr11-534288-C-Achr11-534288-C-Gchr11-534288-C-T

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin 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 criteria provided, multiple submitters, no conflicts P:13
• 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:):

ACMG classification

Verdict is Pathogenic. Variant got 26 ACMG points.

• PS1: Transcript NM_005343.4 (HRAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1209208
• 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, 0.981
• 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/exons	MANE	UniProt
HRAS	NM_005343.4	c.35G>T	p.Gly12Val	missense_variant	2/6	ENST00000311189.8
HRAS	NM_176795.5	c.35G>T	p.Gly12Val	missense_variant	2/6	ENST00000417302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRAS	ENST00000311189.8	c.35G>T	p.Gly12Val	missense_variant	2/6	1	NM_005343.4	P1
HRAS	ENST00000417302.7	c.35G>T	p.Gly12Val	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:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 07, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 05, 2011	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jun 04, 2014	- -

Malignant tumor of urinary bladder Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2012

- -

Epidermal nevus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2012

- -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2016

p.Gly12Val (GGC>GTC): c.35 G>T in exon 2 of the HRAS gene (NM_005343.2). This mutation as well as other mutations leading to the G12V substitution have been reported in individuals with Costello syndrome (Burkitt-Wright et al., 2012). This mutation is associated with a very severe presentation that has been associated with death in the first weeks of life (Burkitt-Wright et al., 2012). The most common features of infants harboring this mutation are severe polyhydramnios, birth weight on or above the 90th percentile, birth occipitofrontal circumference (OFC) on or above the 90th percentile, coarsening of facial features, unusual hand position, unusual foot position, short neck, cardiac hypertrophy, ventilator dependence, death before 6 weeks postnatal age (Burkitt-Wright et al., 2012). In fact, >90% of pathogenic HRAS mutations alter the conserved glycine residues at positions 12 and 13 (Aoki et al., 2005; Gripp et al., 2006). The G12V mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s). -

Myopathy, congenital, with excess of muscle spindles Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2012

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

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. -

Thyroid tumor Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

HRAS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2023

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	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.4	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
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	D
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

Other links and lift over

dbSNP: rs104894230; hg19: chr11-534288; COSMIC: COSV54236734; COSMIC: COSV54236734;