NM_006767.4:c.1397G>A

Variant names:

• chr22-20993967-G-A
• rs587777180
• NM_006767.4:c.1397G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_006767.4(LZTR1):​c.1397G>A​(p.Arg466Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001437345: Publications also reported experimental evidence, and demonstrated that the variant increased Ras signaling, and resulted in impaired subcellular location (Steklov_2018, Bigenzahn_2018).; SCV001503248: Experimental studies have shown that this missense change affects LZTR1 function (PMID:30442762).; SCV004564302: Consistent with predictions, functional studies suggest the variant protein has altered cellular localization, reduced interaction with the binding partner protein CUL3, and is associated with elevated levels of Ras signaling (Bigenzahn 2018, Steklov 2018). PMID:30442766. PMID:30442762.; SCV002701699: One functional study suggested that this alteration may impair complex formation with CUL3 and cellular localization (Steklov M et al. Science, 2018 12;362:1177-1182).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: LZTR1 NM_006767.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.76
• Publications: 7 publications found

Genes affected

LZTR1 (HGNC:6742): (leucine zipper like post translational regulator 1) This gene encodes a member of the BTB-kelch superfamily. Initially described as a putative transcriptional regulator based on weak homology to members of the basic leucine zipper-like family, the encoded protein subsequently has been shown to localize exclusively to the Golgi network where it may help stabilize the Gogli complex. Deletion of this gene may be associated with DiGeorge syndrome. [provided by RefSeq, Jul 2008]

LZTR1 Gene-Disease associations (from GenCC):

• LZTR1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Noonan syndrome 10

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• schwannomatosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Noonan syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• Costello syndrome

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• cardiofaciocutaneous syndrome

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000285314 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001437345: Publications also reported experimental evidence, and demonstrated that the variant increased Ras signaling, and resulted in impaired subcellular location (Steklov_2018, Bigenzahn_2018).; SCV001503248: Experimental studies have shown that this missense change affects LZTR1 function (PMID: 30442762).; SCV004564302: Consistent with predictions, functional studies suggest the variant protein has altered cellular localization, reduced interaction with the binding partner protein CUL3, and is associated with elevated levels of Ras signaling (Bigenzahn 2018, Steklov 2018). PMID: 30442766. PMID: 30442762.; SCV002701699: One functional study suggested that this alteration may impair complex formation with CUL3 and cellular localization (Steklov M et al. Science, 2018 12;362:1177-1182).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 53 uncertain in NM_006767.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-20993967-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1312561.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 22-20993967-G-A is Pathogenic according to our data. Variant chr22-20993967-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 101038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006767.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	NM_006767.4	MANE Select	c.1397G>A	p.Arg466Gln	missense	Exon 13 of 21	NP_006758.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	ENST00000646124.2	MANE Select	c.1397G>A	p.Arg466Gln	missense	Exon 13 of 21	ENSP00000496779.1	Q8N653
	LZTR1	ENST00000888029.1		c.1397G>A	p.Arg466Gln	missense	Exon 13 of 21	ENSP00000558088.1
	LZTR1	ENST00000888032.1		c.1394G>A	p.Arg465Gln	missense	Exon 13 of 21	ENSP00000558091.1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000323 AC: 8 AN: 247306 AF XY: 0.0000298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000956

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1460350 Hom.: 0 Cov.: 34 AF XY: 0.0000330 AC XY: 24 AN XY: 726432

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26062

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86042

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111840

Other (OTH) AF: 0.0000663 AC: 4 AN: 60344

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152240 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74384

African (AFR) AF: 0.0000723 AC: 3 AN: 41472

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000904 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	LZTR1-related schwannomatosis (2)
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
1	-	-	Noonan syndrome 2 (1)
1	-	-	Noonan syndrome 2;C3810283:LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	Schwannomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.74
MPC		0.37
ClinPred		0.89	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.87
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777180; hg19: chr22-21348256; COSMIC: COSV53145166; COSMIC: COSV53145166;