NM_006767.4(LZTR1):c.1939A>G (p.Ile647Val) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 30, 2024
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:: RCV001773446.7

Allele description [Variation Report for NM_006767.4(LZTR1):c.1939A>G (p.Ile647Val)]

NM_006767.4(LZTR1):c.1939A>G (p.Ile647Val)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

22q11.21

Genomic location:

Preferred name:

NM_006767.4(LZTR1):c.1939A>G (p.Ile647Val)

HGVS:

NC_000022.11:g.20995023A>G
NG_034193.1:g.17755A>G
NM_006767.4:c.1939A>GMANE SELECT
NP_006758.2:p.Ile647Val
LRG_989t1:c.1939A>G
LRG_989:g.17755A>G
LRG_989p1:p.Ile647Val
NC_000022.10:g.21349312A>G
NC_000022.10:g.21349312A>G
NM_006767.3:c.1939A>G

Protein change:

I647V

Links:

dbSNP: rs148916790

NCBI 1000 Genomes Browser:

rs148916790

Molecular consequence:

NM_006767.4:c.1939A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002003483	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 25, 2023)	germline	clinical testing	Citation Link,
SCV002176344	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 30, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25795793, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002003483

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 25, 2023)

germline

clinical testing

Citation Link,

SCV002176344

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 30, 2024)

germline

clinical testing

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

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

Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.

Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A, Cristian I, Buscarilli M, Naslavsky MS, Malaquias AC, Zatz M, Bodamer O, Majewski J, Jorge AA, Pereira AC, Kim CA, Passos-Bueno MR, Bertola DR.

J Med Genet. 2015 Jun;52(6):413-21. doi: 10.1136/jmedgenet-2015-103018. Epub 2015 Mar 20.

PubMed [citation]

PMID:: 25795793

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV002003483.4

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with Noonan syndrome who also harbored a variant in the SOS2 gene in published literature (Yamamoto et al., 2015); This variant is associated with the following publications: (PMID: 25795793)

#	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, SCV002176344.3

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 647 of the LZTR1 protein (p.Ile647Val). This variant is present in population databases (rs148916790, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical diagnosis of Noonan syndrome (PMID: 25795793). ClinVar contains an entry for this variant (Variation ID: 928950). 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 not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant 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: Jun 17, 2024

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