11-534289-C-T

Variant names:

• chr11-534289-C-T
• rs104894229
• NM_005343.4:c.34G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005343.4(HRAS):​c.34G>A​(p.Gly12Ser) variant causes a missense change. 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 (★★★). ClinVar reports functional evidence for this variant: "SCV000616364: "In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:46 O:1
• Conservation: PhyloP100: 6.09
• Publications: 181 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000616364: "In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879)."; SCV001362310: At least two publication report experimental evidence evaluating an impact on protein function (Gain of function) and the effect of this variant is similar to other HRAS pathogenic variants (Paquin_2009, Niihori_2011).; SCV002058657: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879).; SCV004037370: in vitro functional studies have demonstrated that this variant may affect protein function (PMID: 17412879); SCV004171305: Functional studies indicate this variant has a damaging effect on the gene or the gene product (van der Burgt I, et. al., 2007).; SCV004801624: Functional studies found that when the p.Gly12Ser variant HRAS protein was over-expressed in human diploid fibroblasts, cells exhibited a senescence phenotype including a flat, enlarged and multivacuolated morphology with prominent nucleoli, in contrast to cells produced by wild type HRAS protein (Niihori et al. 2011). In addition, cells expressing the p.Gly12Ser variant HRAS protein exhibited increased cell proliferation and astrogenesis, but decreased neurogenesis (Paquin et al. 2009).; SCV000207842: "Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey et al. 2013);"; SCV000603969: Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. References: Aoki Y et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005; 37(10):1038-40. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011; 56(10):707-15.; SCV002615093: Functional analysis demonstrated that protein products containing the p.G12S alteration have increased binding of GTP, resulting in increased amounts of the active form the HRAS protein (Wey, 2013). Additionally, patient cell lines with the p.G12S alteration were found to have reduced expression of C4ST-1 mRNA compared to wild type (Kluppel 2012), and in vivo studies showed abnormal neuronal cell proliferation and astrogenesis (Paquin, 2009).; SCV004104104: Functional studies demonstrate increased GTP-bound HRAS (active state) in cells transfected with the p.Gly12Ser variant, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Niihori et al. 2011. PubMed ID: 21850009).; SCV005199936: Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011); SCV004176909: Functional studies show that this variant promotes enhanced MEK, ERK, and AKT phosphorylation and growth-factor independent proliferation, indicating that this variant impacts protein function (Gremer L et al., PMID: 19995790; Denayer E et al., PMID: 17979197).
• 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-534287-GC-AA is described in ClinVar as Pathogenic. ClinVar VariationId is 1209208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 11-534289-C-T is Pathogenic according to our data. 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.34G>A	p.Gly12Ser	missense	Exon 2 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.34G>A	p.Gly12Ser	missense	Exon 2 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.34G>A	p.Gly12Ser	missense	Exon 2 of 5	NP_001123914.1	X5D945

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.34G>A	p.Gly12Ser	missense	Exon 2 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.34G>A	p.Gly12Ser	missense	Exon 2 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.34G>A		non_coding_transcript_exon	Exon 2 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
24	-	-	Costello syndrome (24)
7	-	-	not provided (7)
2	-	-	Noonan syndrome 1 (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Epidermal nevus (1)
1	-	-	EPIDERMAL NEVUS WITH UROTHELIAL CANCER, SOMATIC (1)
1	-	-	HRAS-related disorder (1)
1	-	-	Lip and oral cavity carcinoma (1)
1	-	-	Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome (1)
1	-	-	Myopathy, congenital, with excess of muscle spindles (1)
1	-	-	Nevus sebaceous (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	RASopathy (1)
1	-	-	Rhabdomyosarcoma (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	0.13
Eigen_PC	Benign	0.059
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.73	N
PhyloP100		6.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.014	D
Polyphen		0.80	P
Vest4		0.83
MutPred		0.95		Gain of glycosylation at G12 (P = 0.0044)
MVP		0.91
MPC		1.6
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894229; hg19: chr11-534289; COSMIC: COSV54237299; COSMIC: COSV54237299;