Submissions for variant NM_006767.4(LZTR1):c.1904C>T (p.Pro635Leu)

gnomAD frequency: 0.00077  dbSNP: rs148677674

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001454598	SCV001658330	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001584206	SCV001821411	likely benign	not specified	2021-08-28	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1904C>T (p.Pro635Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250026 control chromosomes. The observed variant frequency is approximately 31 fold of the estimated maximal expected allele frequency for a pathogenic variant in LZTR1 causing Noonan Syndrome phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1904C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001454598	SCV002552608	uncertain significance	not provided	2022-07-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published in association with disease to our knowledge; This variant is associated with the following publications: (PMID: 25795793, 24362817, 33792302)
Ambry Genetics	RCV002413371	SCV002722006	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-08-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001454598	SCV003815325	uncertain significance	not provided	2021-05-11	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Stanford Medicine	RCV003494569	SCV004244376	uncertain significance	Schwannomatosis 2	2021-03-27	criteria provided, single submitter	clinical testing	• The p.Pro635Leu variant in the LZTR1 gene has not been previously reported in association with disease. • This variant has been identified in 58/24,764 (0.23%) African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This allele frequency is greater than would be expected to be disease-causing for autosomal dominant disease. • The LZTR1 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation.• Computational tools predict that the p.Pro635Leu variant does not impact protein function; however, the accuracy of in silico algorithms is limited. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro635Leu variant is uncertain; however, population frequency data suggests that this variant is more likely to be benign than pathogenic. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP2]
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000499922	SCV000590942	likely pathogenic	Noonan syndrome 10	2017-04-26	no assertion criteria provided	clinical testing	This mutation has been reported in 1000 genomes and ExAC databases with allele frequency 0.04% and 0.022%. However, this variant is reported as damaging by SIFT, LRT and MutationTaster.
PreventionGenetics, part of Exact Sciences	RCV004535572	SCV004750623	likely benign	LZTR1-related disorder	2019-06-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).