NM_005343.4(HRAS):c.508A>T (p.Lys170Ter) AND Costello syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 27, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000551172.12

Allele description [Variation Report for NM_005343.4(HRAS):c.508A>T (p.Lys170Ter)]

NM_005343.4(HRAS):c.508A>T (p.Lys170Ter)

Genes:

HRAS:HRas proto-oncogene, GTPase [Gene - OMIM - HGNC]
LRRC56:leucine rich repeat containing 56 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_005343.4(HRAS):c.508A>T (p.Lys170Ter)

Other names:

p.K170*:AAG>TAG; NM_005343.3(HRAS):c.508A>T

HGVS:

NC_000011.10:g.532698T>A
NG_007666.1:g.7853A>T
NM_001130442.3:c.508A>T
NM_001318054.2:c.271A>T
NM_005343.4:c.508A>TMANE SELECT
NM_176795.5:c.*77A>T
NP_001123914.1:p.Lys170Ter
NP_001304983.1:p.Lys91Ter
NP_005334.1:p.Lys170Ter
LRG_506t1:c.508A>T
LRG_506:g.7853A>T
LRG_506p1:p.Lys170Ter
NC_000011.9:g.532698T>A
NM_005343.2:c.508A>T
NM_176795.3:c.*77A>T

Protein change:

K170*

Links:

dbSNP: rs372936166

NCBI 1000 Genomes Browser:

rs372936166

Molecular consequence:

NM_176795.5:c.*77A>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001130442.3:c.508A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001318054.2:c.271A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_005343.4:c.508A>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Costello syndrome (CSTLO)
Synonyms:: FACIOCUTANEOSKELETAL SYNDROME; FCS SYNDROME
Identifiers:: MONDO: MONDO:0009026; MedGen: C0587248; Orphanet: 3071; OMIM: 218040

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000635092	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 12, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000927031	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Uncertain significance (Jun 27, 2019)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000635092

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 12, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000927031

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Uncertain significance
(Jun 27, 2019)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000635092.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change creates a premature translational stop signal (p.Lys170*) in the HRAS gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HRAS cause disease. This variant is present in population databases (rs372936166, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 40447). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV000927031.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.508A>T (p.Lys170Ter) variant in the HRAS gene has been identified in patients with cancer and individuals who underwent testing for RASopathies, however it was also identified in an unaffected parent (BS4; Invitae, GeneDx internal data, GTR Lab ID: 26957, 500031; SCV000207840.14, SCV000635092.3). The filtering allele frequency of the p.Lys170Ter variant is 0.0034% for European (non-Finnish) chromosomes by the gnomAD aggregation database (8/249358 with 95% CI), which is not a high enough frequency to meet thresholds defined by the ClinGen RASopahty Expert panel for autosomal dominant RASopathy variants (BA1/BS1 not met). Furthermore, LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore the PVS1 rule is not applicable. In summary, the clinical significance of the p.Lys170Ter variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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