Submissions for variant NM_006767.4(LZTR1):c.370GTC[1] (p.Val125del)

dbSNP: rs755783378

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000997873	SCV001153627	likely pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000997873	SCV001987713	likely pathogenic	not provided	2024-09-20	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25335493, 30368668, 27921248, 30481304)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805965	SCV002051283	uncertain significance	not specified	2021-12-20	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.373_375delGTC (p.Val125del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 8e-06 in 251242 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.373_375delGTC has been reported in the literature in one individual affected with Schwannomatosis (Paganini_2015). The report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002354912	SCV002624626	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-12-29	criteria provided, single submitter	clinical testing	The c.373_375delGTC variant (also known as p.V125del) is located in coding exon 4 of the LZTR1 gene. This variant results from an in-frame GTC deletion at nucleotide positions 373 to 375. This results in the in-frame deletion of a valine at codon 125. This variant has been reported in a 46 year-old individual with three lower limb schwannomas (Paganini I et al. Eur J Hum Genet, 2015 Jul;23:963-8). Based on internal analysis, the p.V125del variant is predicted to be structurally deleterious. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000997873	SCV002985337	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	This variant, c.373_375del, results in the deletion of 1 amino acid(s) of the LZTR1 protein (p.Val125del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755783378, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of schwannomatosis (PMID: 25335493). ClinVar contains an entry for this variant (Variation ID: 809328). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Baylor Genetics	RCV004569841	SCV005060705	uncertain significance	Schwannomatosis 2	2023-11-22	criteria provided, single submitter	clinical testing