11-534259-G-T

Position:

• chr11-534259-G-T

Variant summary

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

The ENST00000311189.8(HRAS):​c.64C>A​(p.Gln22Lys) 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 (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: HRAS ENST00000311189.8 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.94

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 (size 185) in uniprot entity RASH_HUMAN there are 67 pathogenic changes around while only 17 benign (80%) in ENST00000311189.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 11-534259-G-T is Pathogenic according to our data. Variant chr11-534259-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534259-G-T is described in UniProt as null. Variant chr11-534259-G-T is described in UniProt as null. Variant chr11-534259-G-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.64C>A	p.Gln22Lys	missense_variant	2/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.64C>A	p.Gln22Lys	missense_variant	2/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.64C>A	p.Gln22Lys	missense_variant	2/6	1	NM_005343.4	ENSP00000309845	P1
HRAS	ENST00000417302.7	c.64C>A	p.Gln22Lys	missense_variant	2/6	5	NM_176795.5	ENSP00000388246

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.64C>A (p.Gln22Lys) variant in HRAS gene has been reported in individuals affected with HRAS-related disorders (van der Burgt et al., 2007; Sheffield et al., 2015). This variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic / Likely Pathogenic. The amino acid change p.Gln22Lys in HRAS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gln at position 22 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Aug 28, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 06, 2018	The p.Gln22Lys variant in HRAS has been reported as de novo in 1 infant with cli nical features of Costello syndrome (Sheffield 2015) and as a de novo variant in 1 toddler with congenital myopathy, transient HCM, hypotonia, low-set ears, and a triangular mouth (van der Burgt 2007). This variant has also been reported in ClinVar (Variation ID# 12609) and was absent from large population databases. C omputational prediction tools and conservation analysis suggest that the p.Gln22 Lys variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Gln22Lys variant is li kely pathogenic. ACMG/AMP Criteria applied: PM2, PM6, PP3, PP2. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2015

The Q22K variant in the HRAS gene has been reported previously in a 13-month-old male with mild transient hypertrophic cardiomyopathy, generalized hypotonia and delayed motor development, excess of muscle spindles, fiber atrophy, postnatal transitory respiratory insufficiency, and poor sucking along with other Noonan-like features (van der Burgt et al., 2007). This variant was reported to have occurred de novo in this individual (van der Burgt et al., 2007). Subsequently, the Q22K variant was reported as a de novo variant in a 3-month-old male with dysmorphic features, a severe fatal manifestation of hypertrophic cardiomyopathy and hyperinsulinemic hypoglycemia (Sheffield et al., 2015). The Q22K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q22K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (G12S, G12C, G12D, G12V, G12A, G13C, G13D) have been reported in the Human Gene Mutation Database in association with Costello syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, this variant is likely pathogenic. -

Myopathy, congenital, with excess of muscle spindles Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D;.;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Uncertain	2.2	M;M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.80
MutPred		0.92		Gain of methylation at Q22 (P = 0.0189);Gain of methylation at Q22 (P = 0.0189);Gain of methylation at Q22 (P = 0.0189);Gain of methylation at Q22 (P = 0.0189);Gain of methylation at Q22 (P = 0.0189);
MVP		0.91
MPC		2.4
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.93

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: rs121917757; hg19: chr11-534259; COSMIC: COSV54249433; COSMIC: COSV54249433;