11-534287-GC-TT

Position:

• chr11-534287-GC-TT

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Moderate PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_005343.4(HRAS):​c.35_36delGCinsAA​(p.Gly12Glu) 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 17 ACMG points.

• PS1: Transcript NM_005343.4 (HRAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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 chr11-534288-C-G is described in Lovd as [Pathogenic].
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-534287-GC-TT is Pathogenic according to our data. Variant chr11-534287-GC-TT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163690.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_36delGCinsAA	p.Gly12Glu	missense_variant		ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.35_36delGCinsAA	p.Gly12Glu	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_36delGCinsAA	p.Gly12Glu	missense_variant		1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.35_36delGCinsAA	p.Gly12Glu	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/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Costello syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 22, 2013

The Gly12Glu variant in HRAS has been reported in one individual with a neonatal presentation of Costello syndrome (Kerr 2006). Several other DNA variants affec ting codon 12 of HRAS are commonly observed in patients with Costello syndrome ( Niihori 2011). In addition this variant has not been identified in large populat ion studies. Glycine (Gly) at this position is highly conserved across evolution arily distinct species, and computational analyses (biochemical amino acid prope rties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein. In summary, this variant is likely pathogenic, though additional studie s are required to fully establish its clinical significance. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2017

The c.35_36delGCinsAA variant resulting in a G12E missense variant in the HRAS gene has been reported previously as de novo and in association with Costello syndrome (Weaver et al., 2014). The c.35_36delGCinsAA was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variants in these populations. The G12E 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. The glycine codons 12 and 13 of RAS proteins within the RAS/MAPK pathway are functionally important for GDP/GTP binding and are considered hot spots" for pathogenic variants (Wey et al. 2013; Gripp et al. 2012). Missense variants in this same residue (G12S, G12C, G12A, G12V, G12D) 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." -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503094; hg19: chr11-534287;