rs727504747

Variant names:

• chr11-533880-GC-AG
• rs727504747
• NM_005343.4:c.175_176delGCinsCT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM6 PM2 PP2 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.175_176delinsCT (p.Ala59Leu) in HRAS was absent from gnomAD (PM2; PMID:29493581). It has been identified as a de novo occurrence (parentage unconfirmed) in 1 individual with clinical features of a RASopathy (PM6, PS4_Supporting; SCV000205760.4, PMID:26918529). Furthermore, the p.Ala59Leu variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of HRAS (PM1; PMID 29493581). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PM1, PM2, PM6, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273607/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.82

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.175_176delGCinsCT	p.Ala59Leu	missense_variant		ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.175_176delGCinsCT	p.Ala59Leu	missense_variant		ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.175_176delGCinsCT	p.Ala59Leu	missense_variant		1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.175_176delGCinsCT	p.Ala59Leu	missense_variant		5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Costello syndrome Pathogenic:1

Aug 14, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala59Leu variant in HRAS has now been identified in one individual with clin ical features of a Noonan spectrum disorder and was not identified in the parent s of this individual. This variant has not been previously reported in the liter ature or identified in large population studies. However, an alanine to threonin e change at the same codon in the HRAS gene has been found to segregate in three individuals within one family, all of whom reportedly have clinical features of the Noonan spectrum (LMM unpublished data). In addition, the alanine amino acid is highly conserved across evolutionarily-distinct species, and computational a nalyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) sugg est that this variant may impact the normal function of the protein. In summary, this variant is likely pathogenic, though additional studies are required to fu lly establish its clinical significance. -

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: rs727504747; hg19: chr11-533880;