NM_005343.4(HRAS):c.127C>T (p.Gln43Ter) AND Costello syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 1, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001959252.3

Allele description [Variation Report for NM_005343.4(HRAS):c.127C>T (p.Gln43Ter)]

NM_005343.4(HRAS):c.127C>T (p.Gln43Ter)

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.127C>T (p.Gln43Ter)

HGVS:

NC_000011.10:g.533929G>A
NG_007666.1:g.6622C>T
NM_001130442.3:c.127C>T
NM_001318054.2:c.-193C>T
NM_005343.4:c.127C>TMANE SELECT
NM_176795.5:c.127C>T
NP_001123914.1:p.Gln43Ter
NP_005334.1:p.Gln43Ter
NP_789765.1:p.Gln43Ter
LRG_506t1:c.127C>T
LRG_506:g.6622C>T
LRG_506p1:p.Gln43Ter
NC_000011.9:g.533929G>A

Protein change:

Q43*

Links:

dbSNP: rs2133991697

NCBI 1000 Genomes Browser:

rs2133991697

Molecular consequence:

NM_001318054.2:c.-193C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001130442.3:c.127C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_005343.4:c.127C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_176795.5:c.127C>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
SCV002256731	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002256731

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 1, 2021)

germline

clinical testing

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

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

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 Invitae, SCV002256731.3

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

Description

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with HRAS-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln43*) 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.

#	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 20, 2024

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