NM_005343.4(HRAS):c.221C>T (p.Thr74Ile) AND Costello syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 16, 2024
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:: RCV003774794.3

Allele description [Variation Report for NM_005343.4(HRAS):c.221C>T (p.Thr74Ile)]

NM_005343.4(HRAS):c.221C>T (p.Thr74Ile)

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.221C>T (p.Thr74Ile)

HGVS:

NC_000011.10:g.533835G>A
NG_007666.1:g.6716C>T
NM_001130442.3:c.221C>T
NM_001318054.2:c.-99C>T
NM_005343.4:c.221C>TMANE SELECT
NM_176795.5:c.221C>T
NP_001123914.1:p.Thr74Ile
NP_005334.1:p.Thr74Ile
NP_789765.1:p.Thr74Ile
LRG_506t1:c.221C>T
LRG_506:g.6716C>T
LRG_506p1:p.Thr74Ile
NC_000011.9:g.533835G>A
NM_005343.2:c.221C>T

Protein change:

T74I

Links:

dbSNP: rs1291306227

NCBI 1000 Genomes Browser:

rs1291306227

Molecular consequence:

NM_001318054.2:c.-99C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001130442.3:c.221C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005343.4:c.221C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_176795.5:c.221C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004693991	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 16, 2024)	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

SCV004693991

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 16, 2024)

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004693991.2

#	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 replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 74 of the HRAS protein (p.Thr74Ile). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 1692888). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 80%. 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

Last Updated: Mar 11, 2025

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