chr11-534288-C-G

Position:

• chr11-534288-C-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000311189.8(HRAS):​c.35G>C​(p.Gly12Ala) 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 ENST00000311189.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• 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 22 ACMG points.

• PS1: Transcript ENST00000311189.8 (HRAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 40430
• PM1: In a strand (size 3) in uniprot entity RASH_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in ENST00000311189.8
• 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, 0.98
• PP5: Variant 11-534288-C-G is Pathogenic according to our data. Variant chr11-534288-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 12603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534288-C-G is described in UniProt as null. Variant chr11-534288-C-G is described in UniProt as null. Variant chr11-534288-C-G is described in UniProt as null. Variant chr11-534288-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.35G>C	p.Gly12Ala	missense_variant	2/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.35G>C	p.Gly12Ala	missense_variant	2/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.35G>C	p.Gly12Ala	missense_variant	2/6	1	NM_005343.4	ENSP00000309845	P1
HRAS	ENST00000417302.7	c.35G>C	p.Gly12Ala	missense_variant	2/6	5	NM_176795.5	ENSP00000388246

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 22, 2024	This variant was found de novo in a child with Costello syndrome. It disrupts the p.Gly12 amino acid residue in HRAS. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). In silico prediction indicates that this missense variant is expected to disrupt HRAS function. This missense change has been observed in individuals with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 21, 2023	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt HRAS function. ClinVar contains an entry for this variant (Variation ID: 12603). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). In at least one individual the variant was observed to be de novo. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2017	Variant summary: The HRAS c.35G>C (p.Gly12Ala) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that this variant increased RAS pathway activation in NIH 3T3 cells (Niihori_JHG_2011) and increased proliferation in Ba/F3 cells (Denayer_HM_2008). The variant of interest has not been found in a large, broad control population, ExAC in 120014 control chromosomes. This variant was reported in multiple Costello syndrome patients, including de novo occurrences (Aoki_NatGen_2005, Robbins_AJMG_2016, Niihori_JHG_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:2

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	GeneDx	Sep 24, 2024	Published functional studies demonstrate a damaging effect caused by increased phosphorylation of ERK, suggesting an activation of the RAS/MAPK pathway (Denayer et al., 2008; Niihori et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17979197, 28027064, 17601930, 30055033, 34845155, 24224811, 21686750, 22317973, 23093928, 16170316, 19035362, 24803665, 27589201, 24169525, 16835863, 30762279, 30885829, 31394527, 31560489, 33482860, 33224014, 37488489, 33057194, 35982159, 34643321, 21850009) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2016

- -

Rhabdomyosarcoma Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

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

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	.;D;.;D;D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D
Polyphen		0.83	P;P;P;P;P
Vest4		0.80
MutPred		0.94		Loss of ubiquitination at K16 (P = 0.1191);Loss of ubiquitination at K16 (P = 0.1191);Loss of ubiquitination at K16 (P = 0.1191);Loss of ubiquitination at K16 (P = 0.1191);Loss of ubiquitination at K16 (P = 0.1191);
MVP		0.93
MPC		2.1
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.96

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: COSV54238174; COSMIC: COSV54238174;