Submissions for variant NM_006767.4(LZTR1):c.27del (p.Gln10fs)

dbSNP: rs587777613

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000680837	SCV000808286	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Observed with a second LZTR1 variant on the opposite allele (in trans) in an individual with autosomal recessive Noonan syndrome (Johnston et al., 2018); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25480913, 27856782, 24362817, 29469822)
CeGaT Center for Human Genetics Tuebingen	RCV000680837	SCV001249399	pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000680837	SCV001578236	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln10Argfs*15) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30368668, 30442762, 30442766, 30481304, 30859559). 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 premature translational stop signal has been observed in individual(s) with Noonan syndrome or schwannomatosis (PMID: 24362817, 25480913, 29469822). 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: 143931). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002433625	SCV002749752	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-02-07	criteria provided, single submitter	clinical testing	The c.27delG pathogenic mutation, located in coding exon 1 of the LZTR1 gene, results from a deletion of one nucleotide at nucleotide position 27, causing a translational frameshift with a predicted alternate stop codon (p.Q10Rfs*15). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in multiple individuals with schwannomatosis, as well as in trans with LZTR1 c.1149+1G>A in an individual with autosomal recessive Noonan syndrome (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Smith MJ et al. Neurology, 2015 Jan;84:141-7; Johnston JJ et al. Genet. Med., 2018 10;20:1175-1185; Louvrier C et al. Neuro-oncology, 2018 06;20:917-929). Loss-of-function variants in LZTR1 are related to an increased risk for schwannomas and autosomal recessive Noonan syndrome; however, such associations with autosomal dominant Noonan syndrome have not been observed (Piotrowski A et al. Nat Genet. 2014 Feb;46:182-7; Yamamoto GL et al. J Med Genet. 2015 Jun;52:413-21; Johnston JJ et al. Genet Med. 2018 10;20:1175-1185). Based on the supporting evidence, this variant is 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 or likely pathogenic variant on the other allele; however, the association of this alteration with autosomal dominant Noonan syndrome is unlikely.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003225720	SCV003807996	pathogenic	Noonan syndrome 10	2022-09-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 supporting, PM3 moderated
Neuberg Centre For Genomic Medicine, NCGM	RCV003388573	SCV004100499	pathogenic	Noonan syndrome 2		criteria provided, single submitter	clinical testing	The frameshift deletion p.Q10Rfs*15 in LZTR1 (NM_006767.4) has been reported previously in association with schwannomatosis as well as with autosomal recessive Noonan syndrome (Piotrowski et al., 2014; Johnston et al., 2018 et al). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been proven to be disease causing.For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003225720	SCV004175834	pathogenic	Noonan syndrome 10	2023-02-14	criteria provided, single submitter	clinical testing	The frameshift c.27del(p.Gln10ArgfsTer15) variant in LZTR1 gene has been reported previously in heterozygous state in multiple individuals affected with LZTR1-related disorders (Johnston JJ, et. al., 2018; Smith MJ, et. al., 2015; Piotrowski A, et. al., 2014). The p.Gln10ArgfsTer15 variant has been reported with allele frequency of 0.006% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Glutamine 10, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Gln10ArgfsTer15. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in this gene have been previously reported to be pathogenic (Bigenzahn JW, et. al., 2018; Steklov M, et. al., 2018). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000133460	SCV004193673	pathogenic	Schwannomatosis 2	2023-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000133460	SCV004806981	pathogenic	Schwannomatosis 2	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000133460	SCV000188495	pathogenic	Schwannomatosis 2	2014-02-01	no assertion criteria provided	literature only