NM_014159.7(SETD2):c.5218C>T (p.Arg1740Trp) AND Luscan-Lumish syndrome

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Feb 21, 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:: RCV000853394.8

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:: Luscan-Lumish syndrome
Identifiers:: MONDO: MONDO:0014791; MedGen: C4085873; OMIM: 616831

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000996274	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 5, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001428660	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 16, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001519904	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 18, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002072512	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002515302	Daryl Scott Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002767319	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 21, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31474318, 25741868
SCV004328234	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31474318, 32710489, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	de novo	yes	2	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

Redefining the Etiologic Landscape of Cerebellar Malformations.

Aldinger KA, Timms AE, Thomson Z, Mirzaa GM, Bennett JT, Rosenberg AB, Roco CM, Hirano M, Abidi F, Haldipur P, Cheng CV, Collins S, Park K, Zeiger J, Overmann LM, Alkuraya FS, Biesecker LG, Braddock SR, Cathey S, Cho MT, Chung BHY, Everman DB, et al.

Am J Hum Genet. 2019 Sep 5;105(3):606-615. doi: 10.1016/j.ajhg.2019.07.019. Epub 2019 Aug 29.

PubMed [citation]

PMID:: 31474318
PMCID:: PMC6731369

See all PubMed Citations (4)

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996274.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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 heterogeneous change in ClinVar by a clinical laboratory (Accession ID: RCV000426759.1). 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	1	not provided	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001428660.1

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

Description

This variant was identified as de novo (maternity and paternity confirmed).

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

From Baylor Genetics, SCV001519904.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

From GeneReviews, SCV002072512.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Only variant known to be assoc w/SETD2-NDD w/MCA

#	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

From Daryl Scott Lab, Baylor College of Medicine, SCV002515302.1

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

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767319.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

A heterozygous missense variant was identified, NM_014159.6(SETD2):c.5218C>T in exon 10 of 21 of the SETD2 gene. This substitution is predicted to create a major amino acid change from an arginine to a tryptophan at position 1740 of the protein; NP_054878.5(SETD2):p.(Arg1740Trp). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is situated within a constrained region. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster) and the variant is not present in the gnomAD population database. This variant has been previously reported pathogenic in a patient with cerebellar malformations (Aldinger, K. A. et al. (2019)). A different variant in the same codon resulting in a change to a glutamine has been reported as a VUS (LOVD). Testing of this patient's parents has indicated this variant is due to a de novo event. Based on information available at the time of curation, this variant has been 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 Invitae, SCV004328234.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1740 of the SETD2 protein (p.Arg1740Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SETD2-related conditions (PMID: 31474318, 32710489). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 388568). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SETD2 protein function. For these reasons, this variant has been classified 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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