NM_006912.6(RIT1):c.268A>G (p.Met90Val) AND Noonan syndrome 8

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Aug 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000762859.22

Allele description

NM_006912.6(RIT1):c.268A>G (p.Met90Val)

Gene:

RIT1:Ras like without CAAX 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_006912.6(RIT1):c.268A>G (p.Met90Val)

HGVS:

NC_000001.11:g.155904472T>C
NG_033885.1:g.11931A>G
NM_001256820.2:c.160A>G
NM_001256821.2:c.319A>G
NM_006912.6:c.268A>GMANE SELECT
NP_001243749.1:p.Met54Val
NP_001243750.1:p.Met107Val
NP_008843.1:p.Met90Val
LRG_1372t1:c.268A>G
LRG_1372:g.11931A>G
LRG_1372p1:p.Met90Val
NC_000001.10:g.155874263T>C
NM_001256821.1:c.319A>G
NM_006912.5:c.268A>G

Protein change:

M107V

Links:

Molecular consequence:

NM_001256820.2:c.160A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001256821.2:c.319A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006912.6:c.268A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Noonan syndrome 8 (NS8)
Identifiers:: MONDO: MONDO:0014143; MedGen: C3809233; Orphanet: 648; OMIM: 615355

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000893220	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001403953	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 19, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 23791108, 24939608, 25959749, 7109146, 27101134, 29734338, 27109146, 28492532
SCV001984804	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 28, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002020797	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 26, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002518979	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002581036	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002769064	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27109146, 34306696, 25741868
SCV003920939	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 15, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004050468	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004562884	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Aug 18, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S, et al.

Am J Hum Genet. 2013 Jul 11;93(1):173-80. doi: 10.1016/j.ajhg.2013.05.021. Epub 2013 Jun 20.

PubMed [citation]

PMID:: 23791108
PMCID:: PMC3710767

Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity.

Gos M, Fahiminiya S, Poznański J, Klapecki J, Obersztyn E, Piotrowicz M, Wierzba J, Posmyk R, Bal J, Majewski J.

Am J Med Genet A. 2014 Sep;164A(9):2310-6. doi: 10.1002/ajmg.a.36646. Epub 2014 Jun 17. No abstract available.

PubMed [citation]

PMID:: 24939608

See all PubMed Citations (10)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000893220.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001403953.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met90 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23791108, 24939608, 25959749, 7109146, 27101134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect RIT1 protein function (PMID: 29734338). This variant has been observed in individual(s) with Noonan syndrome (PMID: 27109146). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 561681). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 90 of the RIT1 protein (p.Met90Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001984804.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant, also known in the literature as c.268A>G (p.Met90Val) based on transcript NM_006912.6, has been previously reported as a de novo heterozygous change in at least two patients with Noonan syndrome (PMID: 27109146, 30293990). Missense variants at the same amino acid residue (p.Met90Ile) and (p.Met90Thr) and at neighboring amino acid residues (p.Tyr89His) and (p.Gly95Ala) have been reported in individuals with Noonan Syndrome (PMID: 23791108, 24939608). Functional studies have demonstrated that this variant leads to increased ERK1/2 phosphorylation compared to wild-type RIT1 (PMID: 29734338). It is absent from the gnomAD population database and thus is presumed to be rare. The c.319A>G (p.Met107Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.319A>G (p.Met107Val) variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020797.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV002518979.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002581036.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769064.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 8, (MIM#615355). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Met90Ile) and p.(Met90Leu) have been reported in at least ten individuals with Noonan Syndrome (PMID: 27109146; ClinVar, internal VCGS cohort). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported de novo in at least three individuals with Noonan Syndrome and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 27109146, 34306696). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV003920939.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004050468.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004562884.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The RIT1 c.268A>G, p.Met90Val variant is reported de novo in the literature in multiple individuals affected with Noonan syndrome (Bercher 2020, Miceikaite 2021, Milosavljevic 2016). This variant is also reported in ClinVar (Variation ID: 561681) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (p.Met90Ile) has been reported in individuals with Noonan syndrome and is considered pathogenic (Aoki 2013, Gos 2014). Computational analyses predict that this variant is deleterious (REVEL: 0.732). Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013 Jul 11;93(1):173-80. PMID: 23791108. Becher N et al. Implementation of exome sequencing in fetal diagnostics-Data and experiences from a tertiary center in Denmark. Acta Obstet Gynecol Scand. 2020 Jun;99(6):783-790. PMID: 32304219. Gos M et al. Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity. Am J Med Genet A. 2014 Sep;164A(9):2310-6. PMID: 24939608. Miceikaite I et al. Prenatal cases with rare RIT1 variants causing severe fetal hydrops and death. Clin Case Rep. 2021 Jul 21;9(7):e04507.PMID: 34306696. Milosavljevic D et al. Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature. Am J Med Genet A. 2016 Jul;170(7):1874-80. PMID: 27109146.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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