ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.485G>A (p.Trp162Ter)

gnomAD frequency: 0.00001  dbSNP: rs1458120855
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001776992 SCV002014030 pathogenic not provided 2021-04-16 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001776992 SCV002216763 pathogenic not provided 2023-06-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1321013). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp162*) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30368668, 30442762, 30442766, 30481304, 30859559).
Ambry Genetics RCV002334691 SCV002639387 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2021-06-08 criteria provided, single submitter clinical testing The p.W162* pathogenic mutation (also known as c.485G>A), located in coding exon 5 of the LZTR1 gene, results from a G to A substitution at nucleotide position 485. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is pathogenic for an increased risk of nerve sheath tumors and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic or likely pathogenic variant on the other allele.
Clinical Genomics Laboratory, Washington University in St. Louis RCV004558646 SCV005047090 pathogenic Noonan syndrome 2; Noonan syndrome 10 2023-12-22 criteria provided, single submitter clinical testing The LZTR1 c.485G>A (p.Trp162Ter) variant was identified at a near heterozygous allelic fraction of 48%, a frequency which may be consistent with it being of germline origin. This variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a pathogenic variant by multiple submitters (ClinVar ID: 1321013). This single nucleotide variant occurs at a highly conserved base position and results in a premature termination codon, which is predicted to lead to nonsense mediated decay. This LZTR1 c.485G>A (p.Trp162Ter) variant is only observed on 6/1,611,462 alleles in the general population (gnomAD v.4.0.0), indicating it is not a common variant. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

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