Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_006767.4(LZTR1):c.2178C>A (p.Tyr726Ter)

CA410779953

522799 (ClinVar)

Gene: LZTR1
Condition: RASopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 7e7f14c1-b9c6-47df-be45-efa1dd51f7af
Approved on: 2024-09-17
Published on: 2024-11-04

HGVS expressions

NM_006767.4:c.2178C>A
NM_006767.4(LZTR1):c.2178C>A (p.Tyr726Ter)
NC_000022.11:g.20996071C>A
CM000684.2:g.20996071C>A
NC_000022.10:g.21350360C>A
CM000684.1:g.21350360C>A
NC_000022.9:g.19680360C>A
NG_034193.1:g.18803C>A
ENST00000700578.1:c.2178C>A
ENST00000415817.2:c.607C>A
ENST00000495142.6:n.2530C>A
ENST00000642151.1:c.2009C>A
ENST00000643578.1:n.2200C>A
ENST00000643710.1:n.1039C>A
ENST00000646124.2:c.2178C>A
ENST00000646506.1:n.2045C>A
ENST00000215739.12:c.2178C>A
ENST00000415354.6:c.607C>A
ENST00000415817.1:c.76C>A
ENST00000439171.5:c.577C>A
ENST00000452988.5:c.340C>A
ENST00000463909.1:n.893C>A
ENST00000479606.5:n.2324C>A
ENST00000498649.1:n.194C>A
NM_006767.3:c.2178C>A
More

Pathogenic

Met criteria codes 3
PM3 PVS1 PM2_Supporting
Not Met criteria codes 3
BA1 BS1 PS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.2178C>A (p.Tyr726Ter) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 18/21 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 1/34568) of the c.2178C>A variant in LZTR1 is 0 for Admixed American chromosomes by gnomAD v2.1.1, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in 1 individual with autosomal recessive RASopathy. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was confirmed in trans by family testing (c.1943-256C>T, 1 PM3 point, PMID:29469822) (PM3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PVS1, PM3, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.1; 9/17/2024)
Met criteria codes
PM3
This variant has been detected in 1 individual with autosomal recessive RASopathy. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was confirmed in trans by family testing (c.1943-256C>T, 1 PM3 point, PMID:29469822) (PM3).
PVS1
The c.2178C>A (p.Tyr726Ter) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 18/21 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PM2_Supporting
The filtering allele frequency (the upper threshold of the 95% CI of 1/34568) of the c.2178C>A variant in LZTR1 is 0 for Admixed American chromosomes by gnomAD v2.1.1, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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