Submissions for variant NM_006767.4(LZTR1):c.1605C>A (p.Tyr535Ter)

dbSNP: rs753347937

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pediatrics, The University of Tokyo	RCV001507319	SCV001712280	pathogenic	Noonan syndrome 2	2021-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002405205	SCV002709569	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-10-12	criteria provided, single submitter	clinical testing	The p.Y535* pathogenic mutation (also known as c.1605C>A), located in coding exon 14 of the LZTR1 gene, results from a C to A substitution at nucleotide position 1605. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This alteration has been detected in an individual with schwannomatosis (Ambry internal data). 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 nerve sheath tumors 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.
CeGaT Center for Human Genetics Tuebingen	RCV003434298	SCV004152220	likely pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	LZTR1: PVS1