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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001445924	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 6, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004119288	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2023)	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

SCV001445924

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 6, 2019)

germline

clinical testing

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

SCV004119288

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

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

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

From PreventionGenetics, part of Exact Sciences, SCV004119288.1

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

#	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: Jun 9, 2024

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