NM_014159.7(SETD2):c.5218C>T (p.Arg1740Trp) AND SETD2 associated neurodevelopmental disorder with multiple congenital anomalies

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 3, 2022
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:: RCV004554776.1

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]

Observations:

Condition(s)

Name:: SETD2 associated neurodevelopmental disorder with multiple congenital anomalies
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005044099	New York Genome Center - PrenatalSEQ	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Feb 3, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005044099

New York Genome Center - PrenatalSEQ

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Pathogenic
(Feb 3, 2022)

de novo

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Genotype-phenotype correlation at codon 1740 of SETD2.

Rabin R, Radmanesh A, Glass IA, Dobyns WB, Aldinger KA, Shieh JT, Romoser S, Bombei H, Dowsett L, Trapane P, Bernat JA, Baker J, Mendelsohn NJ, Popp B, Siekmeyer M, Sorge I, Sansbury FH, Watts P, Foulds NC, Burton J, Hoganson G, Hurst JA, et al.

Am J Med Genet A. 2020 Sep;182(9):2037-2048. doi: 10.1002/ajmg.a.61724. Epub 2020 Jul 24.

PubMed [citation]

PMID:: 32710489

Details of each submission

From New York Genome Center - PrenatalSEQ, SCV005044099.1

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

Description

The de novo c.5218C>T (p. Arg1740Trp) missense variant identified in exon 10 (of 21) of the SETD2 gene has been reported as heterozygous de novo in at least 12 individuals affected with SETD2-NDD with MCA [PMID: 32710489; group1 in the article]. A different missense variant (p.Arg1740Gln) affecting the same codon Arg1740 has been reported in 3 individuals (PMID: 32710489; group2 in the article). The c.5218C>T (p. Arg1740Trp) variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. This variant has been reported in the ClinVar database with conflicting interpretations of pathogenicity [likely pathogenic (3), pathogenic (2), and variant of uncertain significance (1). Variation ID: 388568]. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools (CADD score = 27.2 and REVEL score = 0.741). Based on the available evidence, the de novo c.5218C>T (p.Arg1740Trp) variant identified in the SETD2 gene is reported as Pathogenic.

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

Last Updated: Jun 9, 2024

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