chr11-534287-GC-TT

Variant names:

• chr11-534287-GC-TT
• rs727503094
• NM_005343.4:c.35_36delGCinsAA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 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. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. G12S) 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
• Publications: 41 publications found

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]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 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, 13 uncertain in NM_005343.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-534289-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12602.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 163690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.35_36delGCinsAA	p.Gly12Glu	missense	N/A	NP_005334.1
	HRAS	NM_176795.5	MANE Plus Clinical	c.35_36delGCinsAA	p.Gly12Glu	missense	N/A	NP_789765.1
	HRAS	NM_001130442.3		c.35_36delGCinsAA	p.Gly12Glu	missense	N/A	NP_001123914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.35_36delGCinsAA	p.Gly12Glu	missense	N/A	ENSP00000309845.7
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.35_36delGCinsAA	p.Gly12Glu	missense	N/A	ENSP00000388246.1
	HRAS	ENST00000493230.5	TSL:1	n.35_36delGCinsAA		non_coding_transcript_exon	Exon 2 of 7	ENSP00000434023.1

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

Aug 22, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 31, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=0/100	disease causing

Splicing

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

Other links and lift over

dbSNP: rs727503094; hg19: chr11-534287;