11-533881-C-T

Position:

• chr11-533881-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2_Supporting PS4_Moderate PP1 PP3

This summary comes from the ClinGen Evidence Repository: The c.175G>A variant in the HRAS gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 59 (p.Ala59Thr). This variant was absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.755 supporting deleterious impact to HRAS function (PP3). This variant resides within a region (amino acids 57 – 64), of HRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). The c.175G>A (p.Ala59Thr) variant has been identified in at least 3 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners Laboratory for Molecular Medicine, Invitae internal data, ClinVar SCV000198374.4, SCV000950586.1). Moreover, this variant has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000198374.4). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM2_Supporting, PP1, PP3 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA176353/MONDO:0009026/046

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 7.77

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]

HRAS (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.175G>A	p.Ala59Thr	missense_variant	3/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.175G>A	p.Ala59Thr	missense_variant	3/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.175G>A	p.Ala59Thr	missense_variant	3/6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.175G>A	p.Ala59Thr	missense_variant	3/6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Costello syndrome Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 23, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 07, 2017	The p.Ala59Thr variant in HRAS has been identified by our laboratory in three af fected relatives with clinical features of a RASopathy disorder. It was absent f rom large population studies. The p.Ala59Thr variant is known to occur in retrov iral ras oncogenes and has been demonstrated to have transforming activity in mu ltiple in vitro studies (Dhar 1982, Tsuchida 1982, Lacal 1986, Barbacid 1987). C omputational prediction tools and conservation analysis support that the variant may impact the protein. However, these in vitro assays and computational analys es may not accurately represent biological function. In addition, our laboratory has identified a different variant associated with RASopathies at the same posi tion (p.Ala59Leu), which suggests that changes to this position are not tolerate d. In summary, although additional studies are required to fully establish its c linical significance, the p.Ala59Thr variant is likely pathogenic. ACMG/AMP Crit eria applied: PM2, PP2, PP3, PS3_Supporting, PS4_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2018	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change results in elevated GTP nucleotide exchange rate in cultured cells (PMID: 3540608, 3004741). This variant has not been reported in the literature in individuals with HRAS-related disease. ClinVar contains an entry for this variant (Variation ID: 40435). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 59 of the HRAS protein (p.Ala59Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -

Non-small cell lung carcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2017

This variant has been reported in the literature as a variant occurring in retro viral ras oncogenes, and has been demonstrated to have transforming activity in some in vitro studies (Barbacid 1987, Tsuchida 1982, Dhar 1982, Lacai 1986). Ala 59 is also highly conserved among distantly related species. -

RASopathy Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Sep 17, 2024

The c.175G>A variant in the HRAS gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 59 (p.Ala59Thr). This variant was absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.755 supporting deleterious impact to HRAS function (PP3). This variant resides within a region (amino acids 57 – 64), of HRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). The c.175G>A (p.Ala59Thr) variant has been identified in at least 3 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners Laboratory for Molecular Medicine, Invitae internal data, ClinVar SCV000198374.4, SCV000950586.1). Moreover, this variant has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000198374.4). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM2_Supporting, PP1, PP3 (Specification Version 2.1, 09/17/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;.;D;D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.9	H;H;H;H;H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Uncertain	0.040	D;D;D;D;D
Polyphen		0.81	P;B;P;B;B
Vest4		0.95
MutPred		0.78		Gain of glycosylation at T58 (P = 0.066);Gain of glycosylation at T58 (P = 0.066);Gain of glycosylation at T58 (P = 0.066);Gain of glycosylation at T58 (P = 0.066);Gain of glycosylation at T58 (P = 0.066);
MVP		0.96
MPC		1.4
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.93
gMVP		0.84

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: rs727503093; hg19: chr11-533881; COSMIC: COSV54244375; COSMIC: COSV54244375;