Submissions for variant NM_006767.4(LZTR1):c.628C>T (p.Arg210Ter)

gnomAD frequency: 0.00010  dbSNP: rs150419186

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760481	SCV000890370	pathogenic	not provided	2022-03-03	criteria provided, single submitter	clinical testing	Nonsense 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; This variant is associated with the following publications: (PMID: 30006736, 29489754, 25335493, 30859559, 29469822)
CeGaT Center for Human Genetics Tuebingen	RCV000760481	SCV001249400	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	LZTR1: PVS1, PM2:Supporting, PS4:Supporting
Baylor Genetics	RCV001330297	SCV001521938	pathogenic	Noonan syndrome 10	2019-07-12	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000760481	SCV002017209	pathogenic	not provided	2021-03-29	criteria provided, single submitter	clinical testing
Invitae	RCV000760481	SCV002187412	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg210*) 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). This variant is present in population databases (rs150419186, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal dominant schwannomatosis or autosomal recessive Noonan syndrome (PMID: 25335493, 29469822, 30859559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 599030). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002290002	SCV002581852	pathogenic	Schwannomatosis 2	2022-08-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002360863	SCV002656646	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-08-18	criteria provided, single submitter	clinical testing	The p.R210* pathogenic mutation (also known as c.628C>T), located in coding exon 7 of the LZTR1 gene, results from a C to T substitution at nucleotide position 628. This changes the amino acid from an arginine to a stop codon within coding exon 7. This alteration has been reported in several individuals with schwannomatosis as well as in patients with features of autosomal recessive Noonan syndrome (Paganini I et al. Eur. J. Hum. Genet. 2015 Jul;23:963-8; Gröbner SN et al. Nature 2018 03;555:321-327; Johnston JJ et al. Genet. Med. 2018 10;20:1175-1185; Kehrer-Sawatzki H et al. Hum. Genet. 2018 Jul;137:543-552; Pagnamenta AT et al. Clin. Genet. 2019 Jun;95:693-703). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003392575	SCV004120641	pathogenic	LZTR1-related condition	2023-12-19	criteria provided, single submitter	clinical testing	The LZTR1 c.628C>T variant is predicted to result in premature protein termination (p.Arg210*). This variant has been reported in a patient with schwannomatosis and was listed as de novo (Paganini et al. 2015. PubMed ID: 25335493). It has also been reported in trans with another LZTR1 variant in unrelated patients with Noonan syndrome (Johnston et al. 2018. PubMed ID: 29469822; Pagnamenta et al. 2019. PubMed ID: 30859559). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21343948-C-T) and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/599030/). Nonsense variants in LZTR1 are expected to be pathogenic for autosomal recessive Noonan syndrome and autosomal dominant susceptibility to schwannomatosis. This variant is interpreted as pathogenic for autosomal recessive Noonan syndrome and autosomal dominant susceptibility to schwannomatosis. However, in the context of autosomal dominant Noonan syndrome it is of uncertain clinical significance.
Genetics and Molecular Pathology, SA Pathology	RCV002290002	SCV004175296	pathogenic	Schwannomatosis 2	2020-03-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002290002	SCV004191278	pathogenic	Schwannomatosis 2	2023-08-31	criteria provided, single submitter	clinical testing
OMIM	RCV000735431	SCV000863566	pathogenic	Noonan syndrome 2	2018-12-17	no assertion criteria provided	literature only