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 label mismatch: LZTR1 vs undefined
  • 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.1149+1G>A

CA322328053

451722 (ClinVar)

Gene: LZTR1
Condition: RASopathy
Inheritance Mode: Autosomal recessive inheritance
UUID: cc8dfc9c-b101-4ef7-ac33-eae1549671b5
Approved on: 2024-12-03
Published on: 2025-03-26

HGVS expressions

NM_006767.4:c.1149+1G>A
NM_006767.4(LZTR1):c.1149+1G>A
NC_000022.11:g.20992370G>A
CM000684.2:g.20992370G>A
NC_000022.10:g.21346659G>A
CM000684.1:g.21346659G>A
NC_000022.9:g.19676659G>A
NG_034193.1:g.15102G>A
ENST00000700578.1:c.1149+1G>A
ENST00000495142.6:n.494+1G>A
ENST00000642151.1:c.980+1G>A
ENST00000643578.1:n.1171+1G>A
ENST00000646124.2:c.1149+1G>A
ENST00000646506.1:n.728+1G>A
ENST00000215739.12:c.1149+1G>A
ENST00000461510.1:n.251G>A
ENST00000479606.5:n.1295+1G>A
ENST00000492480.1:n.205+1G>A
ENST00000497716.5:n.976+1G>A
NM_006767.3:c.1149+1G>A
More

Likely Pathogenic

Met criteria codes 3
PVS1_Moderate PM3_Strong PM2_Supporting
Not Met criteria codes 2
BS1 BA1

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 1.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1149+1G>T variant in LZTR1 occurs within the canonical splice donor site (+1) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/21, resulting in an in-frame deletion (removes amino acids 332-383) that is predicted to escape nonsense mediated decay (PVS1_Moderate). The filtering allele frequency (the upper threshold of the 95% CI of 1/34210) of the c.1149+1G>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 3 individuals with RASopathy. Of those individuals, all were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by parental testing (c.1339T>G (p.Phe447Val), c.993+1G>A, c.27delG p.Q10fs, 2.25 PM3 points, PMID: 29469822, SCV000620457.7, GeneDx) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM3_Strong, PVS1_Moderate, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024)
Met criteria codes
PVS1_Moderate
The c.1149+1G>T variant in LZTR1 occurs within the canonical splice donor site (+1) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/21, resulting in an in-frame deletion (removes amino acids 332-383) that is predicted to escape nonsense mediated decay (PVS1_Moderate).
PM3_Strong
This variant has been detected in 3 individuals with RASopathy. Of those individuals, all were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by parental testing (c.1339T>G (p.Phe447Val), c.993+1G>A, c.27delG p.Q10fs, 2.25 PM3 points, PMID: 29469822, SCV000620457.7, GeneDx) (PM3_Strong).
PM2_Supporting
The filtering allele frequency (the upper threshold of the 95% CI of 1/34210) of the c.1149+1G>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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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