Submissions for variant NM_006767.4(LZTR1):c.2044A>G (p.Lys682Glu)

gnomAD frequency: 0.00001  dbSNP: rs758472207

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520720	SCV000618378	uncertain significance	not provided	2024-08-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV001250477	SCV001364066	likely pathogenic	Noonan syndrome 2		criteria provided, single submitter	clinical testing	Bi-allelic mutations in the LZTR1 gene have been described as causative for autosomal recessive Noonan Syndrome 2 (MIM # 600574). Johnston et al. recently published 23 affected individuals from 12 families with Noonan syndrome 2. Umeki et al. recently published another case with Noonan syndrome 2. The maternally inherited sequence variant c.2044A>G in the LZTR1 gene has been described twice in gnomAD in heterozygous state in the European population (allele frequency of 0.002%). Prediction programs classify the amino acid exchange from lysine to glutamate at position 682 on the protein level as predominantly pathogenic. The sequence change is located in the BTB domain of the LZTR1 protein. Several missense mutations in this domain have already been described as the cause of autosomal recessive Noonan Syndrome 2 (Johnston et al. 2018). Since the maternally inherited variant is compound heterozygous with a pathogenic variant (paternally inherited, see below) (in trans position), we classify the maternally inherited sequence variant as probably pathogenic according to the ACMG criteria (class IV).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520720	SCV002205294	uncertain significance	not provided	2024-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 682 of the LZTR1 protein (p.Lys682Glu). This variant is present in population databases (rs758472207, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449911). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002420310	SCV002723071	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-02-23	criteria provided, single submitter	clinical testing	The p.K682E variant (also known as c.2044A>G), located in coding exon 17 of the LZTR1 gene, results from an A to G substitution at nucleotide position 2044. The lysine at codon 682 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.