Submissions for variant NM_006767.4(LZTR1):c.2325G>T (p.Gln775His)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002457604	SCV002736900	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-12-04	criteria provided, single submitter	clinical testing	The p.Q775H variant (also known as c.2325G>T), located in coding exon 19 of the LZTR1 gene, results from a G to T substitution at nucleotide position 2325. The amino acid change results in glutamine to histidine at codon 775, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 19, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution, this is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785707	SCV003921811	uncertain significance	Noonan syndrome 2	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative is a likely mechanism of disease in this gene associated with autosomal dominant Noonan syndrome (MIM#616564). Loss of function is a potential mechanism of disease in this gene 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) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0600 - Variant is located in the annotated BACK domain (NCBI Conserved domain). (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 in the public LOVD database with no provided evidence. (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) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV003465754	SCV004191300	uncertain significance	LZTR1-related schwannomatosis	2023-08-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003775189	SCV004676510	uncertain significance	not provided	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 775 of the LZTR1 protein (p.Gln775His). This variant also falls at the last nucleotide of exon 19, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 1789645). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.