rs727503094

Positions:

• chr11-534287-GC-AA
• chr11-534287-GC-AG
• chr11-534287-GC-AT
• chr11-534287-GC-TA
• chr11-534287-GC-TT

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_005343.4(HRAS):​c.35_36delGCinsTT​(p.Gly12Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.82

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: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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a strand (size 3) in uniprot entity RASH_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-534287-GC-AA is Pathogenic according to our data. Variant chr11-534287-GC-AA is described in ClinVar as [Pathogenic]. Clinvar id is 1209208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.35_36delGCinsTT	p.Gly12Val	missense_variant		ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.35_36delGCinsTT	p.Gly12Val	missense_variant		ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.35_36delGCinsTT	p.Gly12Val	missense_variant		1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.35_36delGCinsTT	p.Gly12Val	missense_variant		5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2021	Variant summary: HRAS c.35_36delinsTT (p.Gly12Val) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 281670 control chromosomes. p.Gly12Val has been reported in the literature in multiple individuals affected with Costello Syndrome (e.g. Quelin_2017). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 29, 2019	The HRAS c.35_36delGCinsTT p.(Gly12Val) missense variant is a recurrent missense variant typically associated a with a severe presentation of Costello syndrome. This variant has been identified in individuals with a phenotype consistent with Costello syndrome (Aoki et al. 2005; van der Burgt et al. 2007; Burkitt-Wright et al. 2012; Altmüller et al. 2017). Collectively, missense variants at p.Gly12 or p.Gly13 account for the majority of disease-causing variants found in individuals with Costello syndrome and many have been shown to have a gain of function effect (Gripp and Lin 2012; Gripp and Rauen 2019). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Based on the available evidence the c.35_36delGCinsTT p.(Gly12Val) variant is classified as pathogenic for Costello syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 09, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 27195699). Experimental studies have shown that this missense change affects HRAS function (PMID: 24224811). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1209208). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 27195699). In at least one individual the variant was observed to be de novo. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Val). RNA analysis indicates that this missense change induces altered splicing and is likely to result in the loss of the initiator methionine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2022

Published functional studies demonstrate increased active GTP-bound HRAS, which upregulates the Ras/MAPK pathway, and a mouse model harboring the Hras G12V variant shows neurological deficits and cognitive impairment (Viosca et al., 2009; Wey et al., 2013); Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27195699, 22325359, 31172278, 19371735, 18823404, 23093928, 22584058, 24224811, 25133308, 16443854, 16170316, 22495892, 29493581) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-534287;