11-534285-C-A

Position:

• chr11-534285-C-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.38G>T​(p.Gly13Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G13C) 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:25
• Conservation: PhyloP100: 6.08

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr11-534286-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12606.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-534285-C-A is Pathogenic according to our data. Variant chr11-534285-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534285-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRAS	NM_005343.4	c.38G>T	p.Gly13Val	missense_variant	2/6	ENST00000311189.8
HRAS	NM_176795.5	c.38G>T	p.Gly13Val	missense_variant	2/6	ENST00000417302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRAS	ENST00000311189.8	c.38G>T	p.Gly13Val	missense_variant	2/6	1	NM_005343.4	P1
HRAS	ENST00000417302.7	c.38G>T	p.Gly13Val	missense_variant	2/6	5	NM_176795.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 30, 2023	The HRAS c.38G>T; p.Gly13Val variant (rs104894226) is reported in the literature in multiple individuals affected with Costello syndrome and Schimmelpenning-Feuerstein-Mims syndrome (Gabriel 2022, Gripp 2011, Lefebvre 2021, Luo 2021). This variant is also reported in ClinVar (Variation ID: 180848) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Asp, Arg, Cys) have been reported in individuals with RASopathies and are considered pathogenic (Gripp 2011, Lefebvre 2021, Luo 2021). Computational analyses predict that this variant is deleterious (REVEL: 0.791). Based on available information, this variant is considered to be pathogenic. References: Gabriel H et al. Trio exome sequencing is highly relevant in prenatal diagnostics. Prenat Diagn. 2022 Jun;42(7):845-851. PMID: 34958143. Gripp KW et al. Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C. Am J Med Genet A. 2011 Apr;155A(4):706-16. PMID: 21438134. Lefebvre M et al. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations. J Med Genet. 2021 Jun;58(6):400-413. PMID: 32732226. Luo Q et al. Expanding mutational spectrum of HRAS by a patient with Schimmelpenning-Feuerstein-Mims syndrome. J Dermatol. 2021 Aug;48(8):1273-1276. PMID: 34109654. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2017	The G13V missense change in the HRAS gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. Nevertheless, the vast majority of pathogenic HRAS germline mutations association with Costello syndrome alter the conserved glycine residues at positions 12 and 13, including the mutations G13D and G13C (Aoki et al., 2005; Estep et al., 2006; Gripp et al., 2006). Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, G13V is not observed in large population cohorts (Lek et al., 2016). -

Costello syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2023	Variant summary: HRAS c.38G>T (p.Gly13Val) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250330 control chromosomes (gnomAD). c.38G>T has been reported in the literature in settings of WES in at least two fetuses affected with multiple congenital abnormalities, including one case where it was confirmed to be de novo, although it is not clear whether these individuals would have met the clinical criteria for Costello or Noonan syndromes, these findings suggest the variant may be associated with disease (e.g. Lefebvre_2021, Gabriel_2022). The variant of interest has also been reported in numerous publications as a somatic mutation found in various types of cancers. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant is associated with an increased rate of guanine nucleotide exchange compared to the WT protein (Wey_2013). Additionally, Glycine 13 is one of the two most mutated amino acids in Costello Syndrome, and several other variants located at codon 13 have been associated with Costello Syndrome (G13C, G13D, G13S; Wey_2013). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Thymoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

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

- -

Squamous cell lung carcinoma 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

- -

KA-like vemurafenib-induced squamous lesions Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Jun 07, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lip and oral cavity carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

B-cell chronic lymphocytic leukemia 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

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Linear nevus sebaceous syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

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

- -

Hepatocellular carcinoma 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

- -

Large congenital melanocytic nevus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Jan 15, 2024

The HRAS c.38G>T (p.Gly13Val) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in an individual with Schimmelpenning-Feuerstein-Mims (SFM) syndrome (Luo Q et al., PMID: 34109654). This variant has been reported in the ClinVar database as pathogenic or likely pathogenic in both somatic and germline states (ClinVar Variation ID: 180848). It has also been reported as a somatic variant in multiple cases in the Catalogue of Somatic Mutations in Cancer (COSMIC, Genomic Mutation ID: COSV54237051). This variant is absent from the general population (gnomAD v4.0.0), indicating that it is not a common variant. Two other variants in the same codon, c.38G>A (p.Gly13Asp) and c.37G>T (p.Gly13Cys), have been reported and are considered pathogenic (ClinVar Variation IDs: 12604 and 12606). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. In support of this prediction, functional studies show that the HRAS c.38G>T (p.Gly13Val) variant causes a higher cellular proportion of the biologically active form of HRAS (Wey M et al., PMID: 24224811). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.38G>T (p.Gly13Val) variant is classified as likely pathogenic. -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	4.5	H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.6	D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.91
MutPred		0.93		Loss of ubiquitination at K16 (P = 0.0907);Loss of ubiquitination at K16 (P = 0.0907);Loss of ubiquitination at K16 (P = 0.0907);Loss of ubiquitination at K16 (P = 0.0907);Loss of ubiquitination at K16 (P = 0.0907);
MVP		0.95
MPC		2.4
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
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: rs104894226; hg19: chr11-534285; COSMIC: COSV54237051; COSMIC: COSV54237051;