11-533553-T-C

Variant names:

• chr11-533553-T-C
• rs104894227
• NM_005343.4:c.350A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PS3_Moderate PS4_Moderate PS2 PP3

This summary comes from the ClinGen Evidence Repository: The c.350A>G variant in the HRAS gene is a missense variant predicted to cause substitution of lysine by arginine at amino acid 117 (p.Lys117Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function (PP3). At least 4 independent occurrences of this variant have been detected in patients with a RASopathy, of which 3 were reported as confirmed de novo cases while 1 was an unconfirmed de novo occurrence (PS2_VeryStrong, PS4_Moderate; PMID:16443854, 17979197, 35595280, 32313153). In vitro functional assays showed that the variant increased RAS/MEK/ERK activation compared to wildtype (PS3_Moderate; PMID:17979197, 21850009). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PS3_Modertae, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256490/MONDO:0021060/046

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 4.14
• Publications: 46 publications found

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]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.350A>G	p.Lys117Arg	missense_variant	Exon 4 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.350A>G	p.Lys117Arg	missense_variant	Exon 4 of 6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.350A>G	p.Lys117Arg	missense_variant	Exon 4 of 6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.350A>G	p.Lys117Arg	missense_variant	Exon 4 of 6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Costello syndrome Pathogenic:3

Jul 09, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Lys117Arg variant has been reported as a de novo variant in 2 individuals wi th clinical features of Costello syndrome (Kerr 2006, Denayer 2008). Functional analyses have shown this variant to activate HRAS (Denayer 2008), and is associa ted with a milder Costello phenotype (Niihori 2011). This variant has been annot ated as a pathogenic allele in the ClinVar database (dbSNP rs104894227) and is d iscussed in the Online Mendelian Inheritance in Man (MIM#190020.0006). In summar y, this variant meets our criteria for a pathogenic variant.

Feb 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Kids Research, The Children's Hospital at Westmead

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not provided Pathogenic:1

Apr 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as this variant causes constitutive activation of the RAS/MAPK pathway and impairs GTP hydrolysis (Denayer et al., 2008; Wey et al., 2013); 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: 24224811, 21850009, 23093928, 16155195, 24803665, 16443854, 17979197, 32313153)

RASopathy Pathogenic:1

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.350A>G variant in the HRAS gene is a missense variant predicted to cause substitution of lysine by arginine at amino acid 117 (p.Lys117Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function (PP3). At least 4 independent occurrences of this variant have been detected in patients with a RASopathy, of which 3 were reported as confirmed de novo cases while 1 was an unconfirmed de novo occurrence (PS2_VeryStrong, PS4_Moderate; PMID: 16443854, 17979197, 35595280, 32313153). In vitro functional assays showed that the variant increased RAS/MEK/ERK activation compared to wildtype (PS3_Moderate; PMID: 17979197, 21850009). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PS3_Modertae, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;D;.;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;.;.;.;.
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;H
PhyloP100		4.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Vest4		0.57
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		-0.093	Neutral
Varity_R		0.96
gMVP		0.86
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104894227; hg19: chr11-533553;