Submissions for variant NM_006767.4(LZTR1):c.2260A>C (p.Asn754His)

gnomAD frequency: 0.00005  dbSNP: rs745755957

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001313046	SCV001503522	uncertain significance	not provided	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 754 of the LZTR1 protein (p.Asn754His). This variant is present in population databases (rs745755957, gnomAD 0.003%). 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: 1014327). 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 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	RCV002447326	SCV002737842	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-17	criteria provided, single submitter	clinical testing	The p.N754H variant (also known as c.2260A>C), located in coding exon 19 of the LZTR1 gene, results from an A to C substitution at nucleotide position 2260. The asparagine at codon 754 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225176	SCV003921810	uncertain significance	Noonan syndrome 10	2021-05-07	criteria provided, single submitter	clinical testing	0103 - Dominant negative is a likely mechanism of disease in this gene and is associated with autosomal dominant Noonan syndrome (MIM#616564). Loss of function is a potential mechanism of disease in this gene and is associated with autosomal recessive Noonan syndrome (MIM#605275) (PMID:30481304). (I) 0108 - This gene is associated with both recessive and dominant disease (PMID:25795793, 29469822). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated BTB/POZ domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as a VUS in the ClinVar database. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV004570737	SCV005060596	uncertain significance	Schwannomatosis 2	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699298	SCV005204619	uncertain significance	not specified	2024-06-19	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2260A>C (p.Asn754His) results in a conservative amino acid change located in the BTB/POZ domain (IPR000210) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 1613328 control chromosomes, predominantly at a frequency of 5.9e-05 within the Non-Finnish European subpopulation in the gnomAD database (v4). This frequency is not significantly higher than estimated for a pathogenic variant in LZTR1 causing Noonan Syndrome 2 (4.5e-05 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2260A>C in individuals affected with Noonan Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1014327). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001313046	SCV005327676	uncertain significance	not provided	2024-03-13	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