rs121917758

chr11-533883-G-Achr11-533883-G-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.173C>T(p.Thr58Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T58T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 9.80

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005343.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-533883-G-A is Pathogenic according to our data. Variant chr11-533883-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12610.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-533883-G-A is described in UniProt as null. Variant chr11-533883-G-A is described in UniProt as null. Variant chr11-533883-G-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRAS	NM_005343.4	c.173C>T	p.Thr58Ile	missense_variant	3/6	ENST00000311189.8
HRAS	NM_176795.5	c.173C>T	p.Thr58Ile	missense_variant	3/6	ENST00000417302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRAS	ENST00000311189.8	c.173C>T	p.Thr58Ile	missense_variant	3/6	1	NM_005343.4	P1
HRAS	ENST00000417302.7	c.173C>T	p.Thr58Ile	missense_variant	3/6	5	NM_176795.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460978 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Costello syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 23, 2014	The Thr58Ile variant in HRAS has been reported in three individuals with clinica l features of Costello syndrome (Gripp 2008, Gripp 2012, LMM unpublished data). It was identified to occur de novo in two of these individuals and segregated w ith disease in one affected relative from one of these families. This variant wa s absent from large population studies. Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partner s.org/LMM). -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.173C>T (p.Thr58Ile) variant in HRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 20112233, 16474405). Also, at least 2 independent occurrences of this variant have been detected in patients with a RASopathy (PS4_Supporting; PMID: 22488832, 18247425, 23321623, 20949621, 16921267). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicities of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1; 29493581). 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). The variant is in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS4_Supporting, PM2, PS1, PM1, PP2, PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Feb 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome (MIM#218040) [PMID: 31222966]. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews).(I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the Ras domain (Decipher; PMID 29493581). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in at least two individuals with Costello syndrome (PMID 18247425; PMID 26888048). It has also been reported in a father and child with an attenuated Costello syndrome phenotype (PMID 22488832). This variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 28, 2018	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in individuals with clinical features of Costello syndrome (PMID: 18247425, 22488832, 26888048). ClinVar contains an entry for this variant (Variation ID: 12610). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 58 of the HRAS protein (p.Thr58Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 12, 2020	PS1, PS4_supporting, PM1, PM2, PP5 The HRAS c.173C>T variant is a single nucleotide change from a cytosine to a thymine at position 173 which is predicted to substitute the amino acid threonine at position 58 in the protein to isoleucine. The variant is located in exon 3. This variant has been reported in the literature in patients with Costello syndrome, and this particular variant appears to be associated with an attenuated phenotype and has been described in a father and son (PMID: 22488832; PMID: 18247425) (PS4_supporting). The variant is in dbSNP (rs121917758) but is absent from population databases (PM2). This variant has been classified by the ClinGen RASopathy Variant Curation Expert Panel as Pathogenic and is reported as Pathogenic in the ClinVar database (Variation ID: 12610) (PP5). This variant was detected in both the affected child and her mother. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

HRAS: PS2, PM1, PM2, PS4:Moderate, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	M;M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.8	D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.97
MutPred		0.96		Loss of glycosylation at T58 (P = 0.0515);Loss of glycosylation at T58 (P = 0.0515);Loss of glycosylation at T58 (P = 0.0515);Loss of glycosylation at T58 (P = 0.0515);Loss of glycosylation at T58 (P = 0.0515);
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121917758; hg19: chr11-533883; COSMIC: COSV54240842; COSMIC: COSV54240842;