chr22-20992878-C-T

Position:

• chr22-20992878-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_006767.4:c.1234C>T (p.Arg412Cys) variant in LZTR1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 412. Evidence supports that this variant is associated with AD NS and is not associated with AR NS. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003850 (1/25972 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.351, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:32981126). Schwannomatosis has not been observed in individuals harboring this variant. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS4_Supporting. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA501019/MONDO:0021060/094

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LZTR1 NM_006767.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:9
• Conservation: PhyloP100: 2.57

Genes affected

LZTR1 (HGNC:6742): (leucine zipper like post translational regulator 1) This gene encodes a member of the BTB-kelch superfamily. Initially described as a putative transcriptional regulator based on weak homology to members of the basic leucine zipper-like family, the encoded protein subsequently has been shown to localize exclusively to the Golgi network where it may help stabilize the Gogli complex. Deletion of this gene may be associated with DiGeorge syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LZTR1	NM_006767.4	c.1234C>T	p.Arg412Cys	missense_variant	11/21	ENST00000646124.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LZTR1	ENST00000646124.2	c.1234C>T	p.Arg412Cys	missense_variant	11/21		NM_006767.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455384 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 412 of the LZTR1 protein (p.Arg412Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 32981126, 33258288; https://abstracts.eurospe.org/hrp/0089/hrp0089p2-p265). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 373089). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 28, 2023	The LZTR1 c.1234C>T; p.Arg412Cys variant (rs747430075) is reported in the literature in two individuals with symptoms of Noonan syndrome (Dempsey 2021, Quaio 2020). This variant is also reported in ClinVar (Variation ID: 373089). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism, but is considered a low confidence variant in the database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.351). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Dempsey E et al. A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review. BJOG. 2021 May;128(6):1012-1019. PMID: 32981126. Quaio CRDC et al. Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases. Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):955-964. PMID: 33258288. -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 30, 2020	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2016	The R412C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The R412C variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2021	Variant summary: LZTR1 c.1234C>T (p.Arg412Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 238628 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1234C>T was reported as a de-novo mutation in one Japanese child with symptoms of Noonan Syndrome in a poster presentation at a scientific meeting (Dateki et al, ESPE, 2018), indicating that the variant may be associated with Noonan Syndrome, however this occurrence has not (to the best of our knowledge) been subsequently published in a peer-reviewed journal. Therefore, this information does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no reports of c.1234C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating an impact on protein function have been published in the literature. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The p.R412C pathogenic mutation (also known as c.1234C>T), located in coding exon 11 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1234. The arginine at codon 412 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in multiple unrelated individuals with features of Noonan syndrome; it has been determined to be the result of a de novo mutation or germline mosaicism in multiple families (Quaio CRDC et al. Am J Med Genet C Semin Med Genet, 2020 Dec;184:955-964; Dempsey E et al. BJOG, 2021 May;128:1012-1019; personal communication with GeneDx, Invitae, and the Hospital for Sick Kids). Based on internal structural analysis, the variant disrupts the Kelch VI motif of the LZTR1 protein, which is important for its regulation of RAS proteins (Nacak TG et al. J Biol Chem, 2006 Feb;281:5065-71; Steklov M et al. Science, 2018 Dec;362:1177-1182; Frattini V et al. Nat Genet, 2013 Oct;45:1141-9; Paladino A et al. J Chem Inf Model, 2021 Apr;61:1875-1888). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is pathogenic for autosomal dominant Noonan syndrome; however, the association of this alteration with an increased risk of LZTR1-related schwannomatosis (SWN) is unknown. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 29, 2021

- -

LZTR1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2023

The LZTR1 c.1234C>T variant is predicted to result in the amino acid substitution p.Arg412Cys. This variant was reported in a patient with increased nuchal translucency and pulmonary stenosis (Table S1 - Dempsey et al. 2020. PubMed ID: 32981126) and was reported as de novo in a patient with unspecified syndromic malformations and cardiovascular disease (Case 127 in Quaio et al. 2020. PubMed ID: 33258288). Additionally, in an unpublished abstract this variant was reported as de novo in an individual with Noonan syndrome (Poster P2-265 - Dateki et al. 2018. European Society for Paediatric Endocrinology Meeting; https://www.postersessiononline.eu/173580348_eu/congresos/57ESPE/aula/-P2_265_57ESPE.pdf). At PreventionGenetics, this variant has been detected in multiple individuals with phenotypes overlapping Noonan syndrome/RASopathies (Internal Data). This variant is reported in 1 out of 238,628 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/22-21347167-C-T) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/373089/). This variant is interpreted as likely pathogenic. -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Jul 01, 2023

- -

Schwannomatosis 2;C4225280:Noonan syndrome 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Non-immune hydrops fetalis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Apr 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.7	D;.
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.61		Loss of disorder (P = 0.0444);Loss of disorder (P = 0.0444);
MVP		0.24
MPC		2.0
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.69
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747430075; hg19: chr22-21347167; COSMIC: COSV53147792; COSMIC: COSV53147792;