11-533869-C-T

Position:

• chr11-533869-C-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.187G>A​(p.Glu63Lys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E63D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS ENST00000311189.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.75

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, 10 uncertain in ENST00000311189.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 11-533869-C-T is Pathogenic according to our data. Variant chr11-533869-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-533869-C-T is described in UniProt as null. Variant chr11-533869-C-T is described in UniProt as null. Variant chr11-533869-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.187G>A	p.Glu63Lys	missense_variant	3/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.187G>A	p.Glu63Lys	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.187G>A	p.Glu63Lys	missense_variant	3/6	1	NM_005343.4	ENSP00000309845	P1
HRAS	ENST00000417302.7	c.187G>A	p.Glu63Lys	missense_variant	3/6	5	NM_176795.5	ENSP00000388246

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:1

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, congenital myopathy with excess of muscle spindles type (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 glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least four individuals, including two de novo events, in individuals described to have congenital myopathy, muscular dystrophy or muscle weakness (PMID: 17412879, 25070542, 26001911; ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutagenesis studies have demonstrated a reduction in GTP hydrolysis and subsequent inceased cell proliferation (PMID: 1362901, 8626650). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2017

The E63K pathogenic variant in the HRAS gene has been reported previously as a de novo variant in several unrelated individuals with congenital myopathy with excess muscle spindles (van der Burgt et al., 2007; Bolocan et al., 2014; Henry et al., 2015). The E63K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E63K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrate that E63K is associated with reduced intrinsic GTPase activity (Nur-E-Kamal et al., 1992). We interpret E63K as a pathogenic variant. -

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	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	.;D;.;D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.5	L;L;L;L;L
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.91
MutPred		0.83		Gain of methylation at E63 (P = 0.0133);Gain of methylation at E63 (P = 0.0133);Gain of methylation at E63 (P = 0.0133);Gain of methylation at E63 (P = 0.0133);Gain of methylation at E63 (P = 0.0133);
MVP		0.94
MPC		2.2
ClinPred		0.99	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121917756; hg19: chr11-533869;