Submissions for variant NM_006767.4(LZTR1):c.985G>A (p.Asp329Asn)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003216357	SCV003911667	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-11-15	criteria provided, single submitter	clinical testing	The p.D329N variant (also known as c.985G>A), located in coding exon 9 of the LZTR1 gene, results from a G to A substitution at nucleotide position 985. The aspartic acid at codon 329 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003459803	SCV004191229	uncertain significance	Schwannomatosis 2	2023-10-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003561235	SCV004282722	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 2496780). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. 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 sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 329 of the LZTR1 protein (p.Asp329Asn).
PreventionGenetics, part of Exact Sciences	RCV004736326	SCV005342255	uncertain significance	LZTR1-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The LZTR1 c.985G>A variant is predicted to result in the amino acid substitution p.Asp329Asn. This variant has been reported, along with another likely pathogenic variant in LZTR1, in an individual with Noonan Syndrome (Table S1, De La Vega et al. 2021. PubMed ID: 34645491). This variant is reported in 0.0057% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.