VCV000809328.39 - ClinVar

NM_006767.4(LZTR1):c.370GTC[1] (p.Val125del)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006767.4(LZTR1):c.370GTC[1] (p.Val125del)

Variation ID: 809328 Accession: VCV000809328.39

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 22q11.21 22: 20987552-20987554 (GRCh38) [ NCBI UCSC ] 22: 21341841-21341843 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 3, 2020	Oct 20, 2024	Sep 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006767.4:c.370GTC[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006758.2:p.Val125del	inframe deletion
NM_006767.4:c.373_375del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_006767.3:c.373_375delGTC
NC_000022.11:g.20987553GTC[1]
NC_000022.10:g.21341842GTC[1]
NG_034193.1:g.10285GTC[1]
LRG_989:g.10285GTC[1]
LRG_989t1:c.370GTC[1]	LRG_989p1:p.Val125del

... more HGVS ... less HGVS

Protein change

V125del

Other names

Canonical SPDI

NC_000022.11:20987551:CGTCGTC:CGTC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs755783378 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LZTR1		-	-	GRCh38 GRCh37	3189	3701

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Sep 20, 2024	RCV000997873.31
not specified	Uncertain significance (1)	criteria provided, single submitter	Dec 20, 2021	RCV001805965.2
Cardiovascular phenotype Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Dec 29, 2022	RCV002354912.4
Schwannomatosis 2	Uncertain significance (1)	criteria provided, single submitter	Nov 22, 2023	RCV004569841.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Dec 20, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002051283.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Publications: PubMed (4) PubMed: 27921248‚ 25335493‚ 30481304‚ 30368668 Comment: Variant summary: LZTR1 c.373_375delGTC (p.Val125del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele … (more) Variant summary: LZTR1 c.373_375delGTC (p.Val125del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 8e-06 in 251242 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.373_375delGTC has been reported in the literature in one individual affected with Schwannomatosis (Paganini_2015). The report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Oct 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002985337.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 25335493 Comment: This variant, c.373_375del, results in the deletion of 1 amino acid(s) of the LZTR1 protein (p.Val125del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.373_375del, results in the deletion of 1 amino acid(s) of the LZTR1 protein (p.Val125del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755783378, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of schwannomatosis (PMID: 25335493). ClinVar contains an entry for this variant (Variation ID: 809328). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. (less)
Uncertain significance (Dec 29, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Hereditary cancer-predisposing syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002624626.3 First in ClinVar: Nov 29, 2022 Last updated: Jun 09, 2024	Comment: The c.373_375delGTC variant (also known as p.V125del) is located in coding exon 4 of the LZTR1 gene. This variant results from an in-frame GTC deletion … (more) The c.373_375delGTC variant (also known as p.V125del) is located in coding exon 4 of the LZTR1 gene. This variant results from an in-frame GTC deletion at nucleotide positions 373 to 375. This results in the in-frame deletion of a valine at codon 125. This variant has been reported in a 46 year-old individual with three lower limb schwannomas (Paganini I et al. Eur J Hum Genet, 2015 Jul;23:963-8). Based on internal analysis, the p.V125del variant is predicted to be structurally deleterious. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Nov 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schwannomatosis 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005060705.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Likely pathogenic (Sep 20, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001987713.5 First in ClinVar: Nov 06, 2021 Last updated: Oct 08, 2024	Comment: In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a … (more) In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25335493, 30368668, 27921248, 30481304) (less)
Likely pathogenic (Feb 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001153627.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1

Comment:

Variant summary: LZTR1 c.373_375delGTC (p.Val125del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 8e-06 in 251242 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.373_375delGTC has been reported in the literature in one individual affected with Schwannomatosis (Paganini_2015). The report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This variant, c.373_375del, results in the deletion of 1 amino acid(s) of the LZTR1 protein (p.Val125del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755783378, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of schwannomatosis (PMID: 25335493). ClinVar contains an entry for this variant (Variation ID: 809328). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Comment:

The c.373_375delGTC variant (also known as p.V125del) is located in coding exon 4 of the LZTR1 gene. This variant results from an in-frame GTC deletion at nucleotide positions 373 to 375. This results in the in-frame deletion of a valine at codon 125. This variant has been reported in a 46 year-old individual with three lower limb schwannomas (Paganini I et al. Eur J Hum Genet, 2015 Jul;23:963-8). Based on internal analysis, the p.V125del variant is predicted to be structurally deleterious. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25335493, 30368668, 27921248, 30481304)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling.	Motta M	Human molecular genetics	2019	PMID: 30481304
Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.	Umeki I	Human genetics	2019	PMID: 30368668
The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis.	Kehrer-Sawatzki H	Human genetics	2017	PMID: 27921248
Expanding the mutational spectrum of LZTR1 in schwannomatosis.	Paganini I	European journal of human genetics : EJHG	2015	PMID: 25335493

Text-mined citations for rs755783378 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_006767.4(LZTR1):c.370GTC[1] (p.Val125del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs755783378 ...