22-20982380-A-AC
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006767.4(LZTR1):c.11dupC(p.Ser6GlnfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_006767.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LZTR1 | NM_006767.4 | c.11dupC | p.Ser6GlnfsTer28 | frameshift_variant | Exon 1 of 21 | ENST00000646124.2 | NP_006758.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Schwannomatosis Pathogenic:1
Variant summary: LZTR1 c.11dupC (p.Ser6GlnfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.11dupC in individuals affected with LZTR1-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 918099). Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014) and recessive Noonan syndrome (Johnston_2018). Based on the evidence outlined above, the variant was classified as pathogenic for the risk of multiple schwannomas and recessive Noonan syndrome. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at