Variant: NM_006767.4(LZTR1):c.848G>A (p.Arg283Gln)

CA410781238

561716 (ClinVar)

Gene: LZTR1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: c8222db2-1fa0-4817-b2bb-713739454635

Approved on: 2024-12-03

Published on: 2025-03-26

HGVS expressions

NM_006767.4:c.848G>A
NM_006767.4(LZTR1):c.848G>A (p.Arg283Gln)
NC_000022.11:g.20991684G>A
CM000684.2:g.20991684G>A
NC_000022.10:g.21345973G>A
CM000684.1:g.21345973G>A
NC_000022.9:g.19675973G>A
NG_034193.1:g.14416G>A
ENST00000700578.1:c.848G>A
ENST00000495142.6:n.193G>A
ENST00000642151.1:c.679G>A
ENST00000643578.1:n.870G>A
ENST00000646124.2:c.848G>A
ENST00000646506.1:n.427G>A
ENST00000215739.12:c.848G>A
ENST00000414985.5:c.*414G>A
ENST00000479606.5:n.994G>A
ENST00000497716.5:n.675G>A
NM_006767.3:c.848G>A

Likely Pathogenic

• Met criteria codes: PS2 PS4_Moderate PM2_Supporting

• Not Met criteria codes: BS1 BP4 BA1 PP3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.3.0

Evidence submitted by expert panel

RASopathy VCEP

The NM_006767.4:c.848G>A variant in LZTR1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 283 (p.Arg283Gln). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.609, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. This variant has been reported in 5 probands with RASopathy (PS4_Moderate; PMID: 30368668, SCV000808536.4, GeneDx). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with RASopathy (PS2; PMID: 30368668, SCV000808536.4, GeneDx). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_Moderate, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024)

Met criteria codes

• PS2: This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with RASopathy (PS2; PMID: 30368668, SCV000808536.4, GeneDx).
• PS4_Moderate: This variant has been reported in 5 probands with RASopathy (PS4_Moderate; PMID: 30368668, SCV000808536.4, GeneDx).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (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
• BP4: 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
• PP3: The computational predictor REVEL gives a score of 0.609, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function.