NM_006767.4(LZTR1):c.1685_1702dup (p.Arg567_Gln568insLeuGluGlnLeuCysArg) AND Noonan syndrome 10

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 10, 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:: RCV002273086.4

Allele description [Variation Report for NM_006767.4(LZTR1):c.1685_1702dup (p.Arg567_Gln568insLeuGluGlnLeuCysArg)]

NM_006767.4(LZTR1):c.1685_1702dup (p.Arg567_Gln568insLeuGluGlnLeuCysArg)

Gene:

LZTR1:leucine zipper like post translational regulator 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

22q11.21

Genomic location:

Preferred name:

NM_006767.4(LZTR1):c.1685_1702dup (p.Arg567_Gln568insLeuGluGlnLeuCysArg)

HGVS:

NC_000022.11:g.20994627_20994644dup
NG_034193.1:g.17359_17376dup
NM_006767.4:c.1685_1702dupMANE SELECT
NP_006758.2:p.Arg567_Gln568insLeuGluGlnLeuCysArg
LRG_989t1:c.1685_1702dup
LRG_989:g.17359_17376dup
LRG_989p1:p.Arg567_Gln568insLeuGluGlnLeuCysArg
NC_000022.10:g.21348906_21348907insTGTGCCGCCTGGAGCAGC
NC_000022.10:g.21348916_21348933dup
NM_006767.3:c.1685_1702dup
NM_006767.3:c.1685_1702dupTGGAGCAGCTGTGCCGCC

Links:

dbSNP: rs1924752851

NCBI 1000 Genomes Browser:

rs1924752851

Molecular consequence:

NM_006767.4:c.1685_1702dup - inframe_insertion - [Sequence Ontology: SO:0001821]

Condition(s)

Name:: Noonan syndrome 10 (NS10)
Identifiers:: MONDO: MONDO:0014693; MedGen: C4225280; Orphanet: 648; OMIM: 616564

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002557684	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 24, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30481304, 25741868
SCV003842988	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Jan 10, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002557684

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 24, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003842988

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Uncertain significance
(Jan 10, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling.

Motta M, Fidan M, Bellacchio E, Pantaleoni F, Schneider-Heieck K, Coppola S, Borck G, Salviati L, Zenker M, Cirstea IC, Tartaglia M.

Hum Mol Genet. 2019 Mar 15;28(6):1007-1022. doi: 10.1093/hmg/ddy412.

PubMed [citation]

PMID:: 30481304

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557684.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Noonan syndrome 10 (MIM#616564). Missense variants in this gene enhance stimulus-dependent RAS-MAPK signaling, consistent with lost LZTR1 function as a negative regulator of this pathway (PMID: 30481304). Susceptibility to schwannomatosis-2 (MIM#615670) requires a somatic second hit and is the result of a loss of function mechanism (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame duplication in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated BTB/POZ domain (DECIPHER). (I) 0705 - No comparable insertion or duplication variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV003842988.1

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

Description

The LZTR1 c.1685_1702dup (p.Leu562_Arg567dup) change inserts eighteen nucleotides at position 1685-1702, resulting in an in-frame duplication of 6 amino acid residues. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing. To our knowledge, in-frame duplications in the LZTR1 gene have not been reported in individuals with Noonan syndrome or Schwannomatosis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

#	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: Sep 29, 2024

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