11-533875-G-T

Position:

• chr11-533875-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_005343.4(HRAS):​c.181C>A​(p.Gln61Lys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.82

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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_005343.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-533874-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 11-533875-G-T is Pathogenic according to our data. Variant chr11-533875-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-533875-G-T is described in UniProt as null. Variant chr11-533875-G-T is described in UniProt as null. Variant chr11-533875-G-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRAS	NM_005343.4	c.181C>A	p.Gln61Lys	missense_variant	3/6	ENST00000311189.8
HRAS	NM_176795.5	c.181C>A	p.Gln61Lys	missense_variant	3/6	ENST00000417302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRAS	ENST00000311189.8	c.181C>A	p.Gln61Lys	missense_variant	3/6	1	NM_005343.4	P1
HRAS	ENST00000417302.7	c.181C>A	p.Gln61Lys	missense_variant	3/6	5	NM_176795.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thyroid cancer, nonmedullary, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Epidermal nevus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Mar 21, 2024

An HRAS c.181C>A (p.Gln61Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in an individual with epidermal nevus (Huang L et al., PMID: 35567308). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic germline variant by two submitters (ClinVar ID: 12601) and has been reported as a somatic variant in multiple cases in the cancer database COSMIC (COSV54236740). This variant is absent from the general population (gnomAD v.4.0.0), indicating that it is not a common variant. Another variant in the same codon, (p.Gln61Arg), has been reported in two individuals with melanocytic nevus (Groesser L et al., PMID: 23337891). The HRAS c.181C>A (p.Gln61Lys) variant resides within an H_N_K_Ras_like domain, amino acids 3-164, of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.181C>A (p.Gln61Lys) variant is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2018

The Q61K missense variant in the HRAS gene has not been previously published as a germline variant in association with RASopathies. However, the Q61K variant is not observed in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution in the GTP nucleotide binding region, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (Q61R) and nearby residues (T58I, G60D/V, E63K) of HRAS have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014). Additionally, variants at the same codon in KRAS (Q61P) and NRAS (Q61P/H/R) have been reported, supporting the functional importance of this region of the protein. We interpret this variant as pathogenic -

Noonan syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 28, 2017

Variant summary: The HRAS c.181C>A (p.Gln61Lys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120996 control chromosomes. This variant has been reported as somatic variant in many cancer samples and has been shown to strongly activate the transforming potential of HRAS gene and produce an 8-10 fold reduction in GTPase activity by functional study (Der_1986). This supports the role of inhibition of GTP hydrolysis resulting in a constitutively activated HRAS protein, consistent with the established mechanism of disease attributed to variants in the HRAS gene. In addition, codon Gln61 has been reported as a hotspot for transforming mutations (Saxowsky_2008), and variant was reported as a somatic variant by Database of Curated Mutations (DoCM) to Likely pathogenic. This variant has not, to our knowledge, been reported as a germline variant in patients with Noonan syndrome and related conditions. Taken together, this variant is classified as likely pathogenic until more evidence becomes available. -

Spermatocytic seminoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

Lip and oral cavity carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.3	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D
Polyphen		0.033	B;B;B;B;B
Vest4		0.89
MutPred		0.75		Gain of ubiquitination at Q61 (P = 0.0238);Gain of ubiquitination at Q61 (P = 0.0238);Gain of ubiquitination at Q61 (P = 0.0238);Gain of ubiquitination at Q61 (P = 0.0238);Gain of ubiquitination at Q61 (P = 0.0238);
MVP		0.92
MPC		1.3
ClinPred		0.98	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.95
gMVP		0.94

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: rs28933406; hg19: chr11-533875; COSMIC: COSV54236740; COSMIC: COSV54236740;