22-20995865-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5
The NM_006767.4(LZTR1):c.2062C>T(p.Arg688Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,612,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R688L) has been classified as Uncertain significance.
Frequency
Consequence
NM_006767.4 missense
Scores
Clinical Significance
Conservation
Publications
- LZTR1-related schwannomatosisInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- Noonan syndrome 10Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
- schwannomatosisInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- Noonan syndromeInheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 2Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp
- breast cancerInheritance: AD Classification: MODERATE Submitted by: G2P
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_006767.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LZTR1 | NM_006767.4 | MANE Select | c.2062C>T | p.Arg688Cys | missense | Exon 17 of 21 | NP_006758.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LZTR1 | ENST00000646124.2 | MANE Select | c.2062C>T | p.Arg688Cys | missense | Exon 17 of 21 | ENSP00000496779.1 | ||
| LZTR1 | ENST00000463909.1 | TSL:1 | n.777C>T | non_coding_transcript_exon | Exon 1 of 4 | ||||
| LZTR1 | ENST00000700578.1 | c.2062C>T | p.Arg688Cys | missense | Exon 17 of 20 | ENSP00000515073.1 |
Frequencies
GnomAD3 genomes 0.0000526 AC: 8AN: 152096Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000443 AC: 11AN: 248230 AF XY: 0.0000518 show subpopulations
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1460692Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 726674 show subpopulations
Age Distribution
GnomAD4 genome 0.0000526 AC: 8AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74290 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
LZTR1-related schwannomatosis Pathogenic:3Uncertain:1
The p.Arg688Cys variant in the LZTR1 gene has been previously reported in 4 unrelated individuals with schwannomatosis who were heterozygous for this variant (Piotrowski et al., 2014; Smith et al., 2015; Steklov et al., 2018). This variant has also been reported in 1 individual with Noonan Syndrome, who was compound heterozygous for this variant (Pagnamenta et al., 2019). The p.Arg688Cys variant was determined to be in trans with a likely pathogenic variant (c.1149+1G>T), consistent with autosomal recessive inheritance (Pagnamenta et al., 2019). The presence of this variant with a likely disease-causing variant on the opposite allele increases suspicion for its pathogenicity. The p.Arg688Cys variant has also been identified in 3/24,262 African/African-Amerian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Additionally, two different amino acid changes, p.Arg688His and p.Arg688Gly, have been previously reported at this residue, although the evidence for these variants is insufficient to classify them as disease-causing. The p.Arg688His variant was reported as heterozygous in a patient with schwannomatosis (Steklov et al., 2018). The p.Arg688Gly variant was reported in trans with a disease-causing variant (c.1943-256C>T) in an individual with Noonan Syndrome (Johnston et al., 2018). Functional studies of this variant have been reported; however, it is currently unclear if this would be sufficientto be disease-causing (Steklov et al., 2018). Computational tools predict that the p.Arg688Cys variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of thep.Arg688Cysvariant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PM3; PP3]
not provided Pathogenic:1Uncertain:1
Reported as de novo in a patient with unexplained developmental delay (DD) or intellectual disability (ID), but this patient also harbored a de novo pathogenic variant in the TCF4 gene which could explain the phenotype (PMID: 33644862); Published functional studies suggest this variant may have an affect on cellular localization of the LZTR1 protein and impairs degradation of substrates of LZTR1-CUL3 ubiquitin ligase (PMID: 36445254, 30442762); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35840934, 29469822, 33792302, 34913528, 25480913, 33407364, 30442762, 24362817, 33644862, 30859559, 39003740, 38333672, 38434521, 36445254, 37436963, 38413718)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 688 of the LZTR1 protein (p.Arg688Cys). This variant is present in population databases (rs587777178, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant schwannomatosis and/or autosomal recessive Noonan syndrome (PMID: 24362817, 25480913, 30859559). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 101036). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LZTR1 function (PMID: 30442762). This variant disrupts the p.Arg688 amino acid residue in LZTR1. Other variant(s) that disrupt this residue have been observed in individuals with LZTR1-related conditions (PMID: 29469822, 30859559), which suggests that this may be a clinically significant amino acid residue. 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.
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
The p.R688C variant (also known as c.2062C>T), located in coding exon 17 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2062. The arginine at codon 688 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in conjunction with LZTR1 c.1149-1G>T (phase unknown) in a patient with a presumed Noonan syndrome diagnosis (Pagnamenta AT et al. Clin. Genet., 2019 Jun;95:693-703). This variant has also been reported in multiple individuals with schwannomatosis (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Smith MJ et al. Neurology, 2015 Jan;84:141-7; Steklov M et al. Science, 2018 12;362:1177-1182). A functional study suggests that this alteration may impair complex formation with CUL3 and affect subcellular localization (Steklov M et al. Science, 2018 12;362:1177-1182). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is likely pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN) and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic variant on the other allele; however, the association of this alteration with autosomal dominant Noonan syndrome is unknown.
Diffuse midline glioma, H3 K27-altered Pathogenic:1
Schwannomatosis Pathogenic:1
Variant summary: LZTR1 c.2062C>T (p.Arg688Cys) results in a non-conservative amino acid change located in the POZ domain (IPR011333) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 248230 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LZTR1 causing Schwannomatosis, allowing no conclusion about variant significance. c.2062C>T has been reported in the heterozygous state in multiple individuals in the literature affected with autosomal dominant Schwannomatosis, and has also been reported in the compound heterozygous state in at least 1 individual with autosomal recessive Noonan syndrome and has further been observed in individuals with acute lymphoblastic leukemia (example, Piotrowski_2014, Pagnamenta_2019, Smith_2015, Steklov_2018, Junk_2024, Williams_2023). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in vitro (example, Steklov_2018), demonstrating this variant loses the ability to properly localize and has diminished interaction with binding partners. The following publications have been ascertained in the context of this evaluation (PMID: 24362817, 30859559, 33644862, 25480913, 30442762, 39003740, 30442766, 38434521, 38413718, 37436963). ClinVar contains an entry for this variant (Variation ID: 101036). Based on the evidence outlined above, the variant was classified as likely pathogenic.
LZTR1-related disorder Pathogenic:1
The LZTR1 c.2062C>T variant is predicted to result in the amino acid substitution p.Arg688Cys. This variant was reported individuals with autosomal dominant schwannomatosis (Piotrowski et al. 2014. PubMed ID: 24362817; Smith et al. 2015. PubMed ID: 25480913, Steklov et al. 2018. PubMed ID: 30442762) and in a patient with autosomal recessive Noonan syndrome (Patient 279914 in Pagnamenta et al. 2019. PubMed ID: 30859559). It was also reported to be de novo in a patient from a cohort of individuals with developmental delay/intellectual disability; however, this patient also had a de novo pathogenic variant in TCF4 (Hiraide et al. 2021. PubMed ID: 33644862). However, one of the cases reported in Piotrowski et al. found that the variant was inherited from an asymptomatic father (Piotrowski et al. 2014. PubMed ID: 24362817). Functional analysis showed that the variant lead to reduced CUL3 binding (Steklov et al. 2018. PubMed ID: 30442762). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21350154-C-T). This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely pathogenic to uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/). Of note, different variants at the same amino acid (p.Arg688Gly and p.Arg688His) have also been reported in a patient with autosomal recessive Noonan syndrome (Johnston et al. 2018. PubMed ID: 29469822) and in patients with schwannomatosis (Steklov et al. 2018. PubMed ID: 30442762). Based on this evidence, we interpret the c.2062C>T (p.Arg688Cys) variant as likely pathogenic.
Noonan syndrome 2;C3810283:LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10 Uncertain:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at