11-533553-T-C

Position:

• chr11-533553-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_005343.4(HRAS):​c.350A>G​(p.Lys117Arg) 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 (★★★).

• 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

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 16 ACMG points.

• PM1: In a chain GTPase HRas, N-terminally processed (size 184) in uniprot entity RASH_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_005343.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 11-533553-T-C is Pathogenic according to our data. Variant chr11-533553-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12605.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-533553-T-C is described in UniProt as null. Variant chr11-533553-T-C is described in UniProt as null. Variant chr11-533553-T-C is described in UniProt as null.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.350A>G	p.Lys117Arg	missense_variant	4/6	1	NM_005343.4	ENSP00000309845	P1
HRAS	ENST00000417302.7	c.350A>G	p.Lys117Arg	missense_variant	4/6	5	NM_176795.5	ENSP00000388246

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Costello syndrome Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.350A>G (p.Lys117Arg) variant in HRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16443854, 16155195). In vitro functional studies provide some evidence that the p.Lys117Arg variant may impact protein function (PS3; PMID 17979197, 21850009). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Lys117Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM1, PM2, PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 09, 2012	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. -
Pathogenic, criteria provided, single submitter	research	Kids Research, The Children's Hospital at Westmead	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 08, 2022

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) -

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	Pathogenic	0.94	.;D;.;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
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
MutationTaster	Benign	1.0	A;A;A;A;A
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
Polyphen		1.0	D;D;D;D;D
Vest4		0.57
MutPred		0.91		Loss of methylation at K117 (P = 0.0042);Loss of methylation at K117 (P = 0.0042);Loss of methylation at K117 (P = 0.0042);Loss of methylation at K117 (P = 0.0042);Loss of methylation at K117 (P = 0.0042);
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.96
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894227; hg19: chr11-533553;