Variant: NM_006767.4(LZTR1):c.850C>T (p.Arg284Cys)

CA204980

209089 (ClinVar)

Gene: LZTR1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 95dbff35-1d45-4617-ab27-bd54c4fdafcd

Approved on: 2024-12-03

Published on: 2025-03-26

HGVS expressions

NM_006767.4:c.850C>T
NM_006767.4(LZTR1):c.850C>T (p.Arg284Cys)
NC_000022.11:g.20991686C>T
CM000684.2:g.20991686C>T
NC_000022.10:g.21345975C>T
CM000684.1:g.21345975C>T
NC_000022.9:g.19675975C>T
NG_034193.1:g.14418C>T
ENST00000700578.1:c.850C>T
ENST00000495142.6:n.195C>T
ENST00000642151.1:c.681C>T
ENST00000643578.1:n.872C>T
ENST00000646124.2:c.850C>T
ENST00000646506.1:n.429C>T
ENST00000215739.12:c.850C>T
ENST00000479606.5:n.996C>T
ENST00000497716.5:n.677C>T
NM_006767.3:c.850C>T

Likely Pathogenic

• Met criteria codes: PS2 PP3 PS3_Moderate PM2_Supporting PS4_Supporting

• Not Met criteria codes: BS3 BS1 BP4 BA1 PP1

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.850C>T variant in LZTR1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 284 (p.Arg284Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.801, which is above the threshold of 0.7, evidence that correlates with impact to LZTR1 function (PP3). This variant has been reported in 1 proband meeting NS diagnostic criteria (PS4_Supporting; PMID:25795793). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with Noonan syndrome (PS2; PMID:25795793). RAS, MEK, and ERK activation in HEK293T cells showed increased level of endogenous active, GTP-bound RAS and increased phosphorylation of MEK and ERK, indicating that this variant impacts protein function (PMID:30481304)(PS3_Moderate). 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, PS3_Moderate, PS4_Supporting, PM2_Supporting, PP3. (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 1 individual with Noonan syndrome (PS2; PMID:25795793).
• PP3: The computational predictor REVEL gives a score of 0.801, which is above the threshold of 0.7, evidence that correlates with impact to LZTR1 function (PP3).
• PS3_Moderate: RAS, MEK, and ERK activation in HEK293T cells showed increased level of endogenous active, GTP-bound RAS and increased phosphorylation of MEK and ERK, indicating that this variant impacts protein function (PMID:30481304)(PS3_Moderate).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PS4_Supporting: This variant has been reported in 1 proband meeting NS diagnostic criteria (PS4_Supporting; PMID:25795793).

Not Met criteria codes

• BS3: 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
• 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
• PP1: PP1_M not applied due to only one segregating family.