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NM_014159.7(SETD2):c.5218C>T (p.Arg1740Trp) AND SETD2-related disorder

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jan 3, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001267684.2

Allele description [Variation Report for NM_014159.7(SETD2):c.5218C>T (p.Arg1740Trp)]

NM_014159.7(SETD2):c.5218C>T (p.Arg1740Trp)

Gene:
SETD2:SET domain containing 2, histone lysine methyltransferase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p21.31
Genomic location:
Preferred name:
NM_014159.7(SETD2):c.5218C>T (p.Arg1740Trp)
HGVS:
  • NC_000003.12:g.47088172G>A
  • NG_032091.1:g.80806C>T
  • NM_001349370.3:c.5086C>T
  • NM_014159.7:c.5218C>TMANE SELECT
  • NP_001336299.1:p.Arg1696Trp
  • NP_054878.5:p.Arg1740Trp
  • NP_054878.5:p.Arg1740Trp
  • LRG_775t1:c.5218C>T
  • LRG_775:g.80806C>T
  • LRG_775p1:p.Arg1740Trp
  • NC_000003.11:g.47129662G>A
  • NM_014159.6:c.5218C>T
  • NR_146158.3:n.5407C>T
Protein change:
R1696W; ARG1740TRP
Links:
OMIM: 612778.0005; dbSNP: rs1057523157
NCBI 1000 Genomes Browser:
rs1057523157
Molecular consequence:
  • NM_001349370.3:c.5086C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014159.7:c.5218C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146158.3:n.5407C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
SETD2-related disorder
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001445924Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Sep 6, 2019) 		germlineclinical testing

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

SCV004119288PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 3, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445924.1

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

Description

This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Multiple in silico analyses support a deleterious effect of the c.5218C>T (p.Arg1740Trp) variant on protein function. This variant has been reported as Pathogenic as a heterozygous change by a clinical laboratory in the ClinVar databse (Variation ID: 388568). Additionally, this variant has been previously identified by our laboratory in a similarly affected individual and in multiple other similarly affected individuals. Based on the available evidence, the c.5218C>T (p.Arg1740Trp) variant is classified as Likely Pathogenic.

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

From PreventionGenetics, part of Exact Sciences, SCV004119288.1

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

Description

The SETD2 c.5218C>T variant is predicted to result in the amino acid substitution p.Arg1740Trp. This variant was reported to be a recurrent de novo variant in more than 10 individuals with Rabin-Pappas syndrome (Rabin et al. 2020. PubMed ID: 32710489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

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

Last Updated: Nov 3, 2024