Submissions for variant NM_006767.4(LZTR1):c.842C>T (p.Pro281Leu)

gnomAD frequency: 0.00003  dbSNP: rs1390048261

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681035	SCV000808488	likely pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Observed in an individual with schwannomatosis (Louvrier et al., 2018); Identified in patients with features consistent with Noonan syndrome previously tested at GeneDx, including as a de novo variant with confirmed parentage; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24362817, 18948947, 29409008)
CeGaT Center for Human Genetics Tuebingen	RCV000681035	SCV001153628	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing	LZTR1: PP3, PS2:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193027	SCV001361561	uncertain significance	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.842C>T (p.Pro281Leu) results in a non-conservative amino acid change located in one of the kelch repeats (IPR006652) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 150946 control chromosomes (gnomAD v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.842C>T has been reported in the literature in an individual affected with schwannomatosis (Louvrier_2018). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV001330298	SCV001521939	uncertain significance	Noonan syndrome 10	2020-02-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV000681035	SCV002245262	likely pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 281 of the LZTR1 protein (p.Pro281Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and/or schwannomatosis (PMID: 29409008; Invitae; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 561683). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002442408	SCV002677796	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-03-13	criteria provided, single submitter	clinical testing	The c.842C>T (p.P281L) alteration is located in exon 9 (coding exon 9) of the LZTR1 gene. This alteration results from a C to T substitution at nucleotide position 842, causing the proline (P) at amino acid position 281 to be replaced by a leucine (L). Based on the available evidence, the LZTR1 c.842C>T (p.P281L) variant is classified as likely pathogenic for autosomal dominant Noonan syndrome; however, the association of this alteration with an increased risk of schwannomas is unknown. Based on data from gnomAD, the T allele has an overall frequency of 0.003% (4/152174) total alleles studied. The highest observed frequency was 0.007% (1/15288) of Admixed American alleles. This variant has been determined to be the result of a de novo mutation in multiple families with features of Noonan syndrome (Ambry internal data; personal communication with GeneDx and ARUP). The variant has been observed in additional individuals with Noonan syndrome (Ambry internal data). In addition, this alteration has been detected in individuals with schwannomas (Louvrier, 2018; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004535697	SCV004113854	likely pathogenic	LZTR1-related disorder	2023-01-30	criteria provided, single submitter	clinical testing	The LZTR1 c.842C>T variant is predicted to result in the amino acid substitution p.Pro281Leu. This variant has been reported in an individual with schwannoma (Table S8 - Louvrier et al. 2018. PubMed ID: 29409008). At PreventionGenetics, this variant has been found to be de novo in an individual with features overlapping with Noonan syndrome (Internal Data). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org). In ClinVar, this variant has conflicting interpretations of uncertain and likely pathogenic with multiple labs reporting the variant was found to be de novo in individuals with features of Noonan syndrome; however, this was not able to be independently verified (https://www.ncbi.nlm.nih.gov/clinvar/variation/561683/). This variant is interpreted as likely pathogenic.