NM_001354689.3(RAF1):c.779C>A (p.Thr260Lys) AND Rasopathy

Clinical significance:Likely pathogenic (Last evaluated: Jul 8, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000792062.1

Allele description [Variation Report for NM_001354689.3(RAF1):c.779C>A (p.Thr260Lys)]

NM_001354689.3(RAF1):c.779C>A (p.Thr260Lys)

Gene:
RAF1:Raf-1 proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.2
Genomic location:
Preferred name:
NM_001354689.3(RAF1):c.779C>A (p.Thr260Lys)
HGVS:
  • NC_000003.12:g.12604191G>T
  • NG_007467.1:g.64989C>A
  • NM_001354689.3:c.779C>AMANE SELECT
  • NM_001354690.2:c.779C>A
  • NM_001354691.2:c.536C>A
  • NM_001354692.2:c.536C>A
  • NM_001354693.2:c.680C>A
  • NM_001354694.2:c.536C>A
  • NM_001354695.2:c.437C>A
  • NM_002880.3:c.779C>A
  • NP_001341618.1:p.Thr260Lys
  • NP_001341619.1:p.Thr260Lys
  • NP_001341620.1:p.Thr179Lys
  • NP_001341621.1:p.Thr179Lys
  • NP_001341622.1:p.Thr227Lys
  • NP_001341623.1:p.Thr179Lys
  • NP_001341624.1:p.Thr146Lys
  • NP_002871.1:p.Thr260Lys
  • LRG_413t1:c.779C>A
  • LRG_413t2:c.779C>A
  • LRG_413:g.64989C>A
  • LRG_413p1:p.Thr260Lys
  • LRG_413p2:p.Thr260Lys
  • NC_000003.11:g.12645690G>T
  • NR_148940.2:n.1110C>A
  • NR_148941.2:n.1110C>A
  • NR_148942.2:n.1110C>A
Protein change:
T146K
Links:
dbSNP: rs869025501
NCBI 1000 Genomes Browser:
rs869025501
Molecular consequence:
  • NM_001354689.3:c.779C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.2:c.779C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.2:c.536C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.2:c.536C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.2:c.680C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.2:c.536C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.2:c.437C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.3:c.779C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.2:n.1110C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.2:n.1110C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.2:n.1110C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Rasopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: CN166718

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000931334Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 16, 2018)
germlineclinical testing

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

SCV001361778Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Jul 8, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000931334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces threonine with lysine at codon 260 of the RAF1 protein (p.Thr260Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Noonan syndrome (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). The observation of one or more missense substitutions at this codon (p.Thr260Arg and p.Thr260Ile) in affected individuals suggests that this may be a clinically significant residue (PMID: 17603483, Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361778.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: RAF1 c.779C>A (p.Thr260Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes (gnomAD) )(ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.779C>A in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Since its previous evaluation by our laboratory, a ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic, reporting it as de novo occurrence in an individual affected with Noonan syndrome (SCV000931334.1) (ACMG PM6). As parental testing was not conducted, this finding has not been independently corroborated at our laboratory. Other variants affecting the same codon or adjacent codons have been classified as pathogenic by our laboratory, in ClinVar database and reported in HGMD database as disease-associated (e.g. S259P, T260P, T260R, P261A, P261S, P261R, P261L), suggesting a possible mutational hotspot important for protein function (ACMG PM5). Nevertheless, at least one variant affecting the same codon (c.779C>T, p.Thr260Ile) is classified as VUS in ClinVar by the ClinGen RASopathy Variant Curation Expert Panel. Based on the evidence outlined above, the variant was re-classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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