NM_006912.6(RIT1):c.170C>G (p.Ala57Gly) AND Noonan syndrome 8

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Oct 25, 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:: RCV000054404.21

Allele description [Variation Report for NM_006912.6(RIT1):c.170C>G (p.Ala57Gly)]

NM_006912.6(RIT1):c.170C>G (p.Ala57Gly)

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.170C>G (p.Ala57Gly)

HGVS:

NC_000001.11:g.155904798G>C
NG_033885.1:g.11605C>G
NM_001256820.2:c.62C>G
NM_001256821.2:c.221C>G
NM_006912.6:c.170C>GMANE SELECT
NP_001243749.1:p.Ala21Gly
NP_001243750.1:p.Ala74Gly
NP_008843.1:p.Ala57Gly
LRG_1372t1:c.170C>G
LRG_1372:g.11605C>G
LRG_1372p1:p.Ala57Gly
NC_000001.10:g.155874589G>C
NM_001256821.1:c.221C>G
NM_006912.4:c.170C>G
NM_006912.5:c.170C>G
Q92963:p.Ala57Gly
p.A57G

Protein change:

A21G; ALA57GLY

Links:

UniProtKB: Q92963#VAR_070150; OMIM: 609591.0001; dbSNP: rs672601334

NCBI 1000 Genomes Browser:

rs672601334

Molecular consequence:

NM_001256820.2:c.62C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001256821.2:c.221C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006912.6:c.170C>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
SCV000082881	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 23791108, 25124994
SCV000541749	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 25, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 23791108, 24901346, 25124994, 26714497, 26757980, 27101134, 25049390, 25959749, 27226556, 28492532
SCV000586722	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001164408	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2018)	de novo	research	PubMed (4) [See all records that cite these PMIDs] 25959749, 26714497, 23791108, 25741868
SCV002020800	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002058169	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:25959749,
SCV003804262	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 2023)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003919073	Duke University Health System Sequencing Clinic, Duke University Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2023)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV004050492	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]

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, research
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The usefulness of whole-exome sequencing in routine clinical practice.

Iglesias A, Anyane-Yeboa K, Wynn J, Wilson A, Truitt Cho M, Guzman E, Sisson R, Egan C, Chung WK.

Genet Med. 2014 Dec;16(12):922-31. doi: 10.1038/gim.2014.58. Epub 2014 Jun 5.

PubMed [citation]

PMID:: 24901346

Further evidence of the importance of RIT1 in Noonan syndrome.

Bertola DR, Yamamoto GL, Almeida TF, Buscarilli M, Jorge AA, Malaquias AC, Kim CA, Takahashi VN, Passos-Bueno MR, Pereira AC.

Am J Med Genet A. 2014 Nov;164A(11):2952-7. doi: 10.1002/ajmg.a.36722. Epub 2014 Aug 13.

PubMed [citation]

PMID:: 25124994

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000082881.2

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

Description

In 4 unrelated patients with Noonan syndrome-8 (NS8; 615355), Aoki et al. (2013) identified a de novo heterozygous c.170C-G transversion in exon 4 of the RIT1 gene, resulting in an ala57-to-gly (A57G) substitution at a conserved residue. In vitro cellular expression studies showed that the A57G mutation resulted in a gain of function.

In 2 unrelated Brazilian patients with NS8, Bertola et al. (2014) identified heterozygosity for the A57G mutation.

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

From Invitae, SCV000541749.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 57 of the RIT1 protein (p.Ala57Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 23791108, 24901346, 25049390, 25124994, 25959749, 26714497, 26757980, 27101134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 60506). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) did not meet the statistical confidence thresholds required to predict the impact of this variant on RIT1 function. Experimental studies have shown that this missense change affects RIT1 function (PMID: 25049390, 25959749, 27226556). For these reasons, this variant has been classified as Pathogenic.

#	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 Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV000586722.1

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

Description

The missense variant c.221C>G, p.(Ala74Gly) in RIT1 was identified in a boy with clinically suspected Noonan syndrome and osteogenesis imperfecta due to a de novo mutation in COL1A1. The variant in RIT1 was shown to be de novo and had been reported in several other patients with Noonan syndrome.

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164408.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (4)

Description

The heterozygous p.Ala74Gly variant in RIT1 was identified by our study in one individual with Noonan syndrome. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported in ClinVar with an alternate name, p.Ala57Gly (Variation ID: 60506). There are at least five individuals with Noonan syndrome and de novo inheritance of this variant in ClinVar and the literature (PMID: 25959749, 26714497, 23791108). In summary, the p.Ala74Gly variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong (Richards 2015).

#	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 Revvity Omics, Revvity, SCV002020800.3

#	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 3billion, SCV002058169.1

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

Description

The variant has been reported as de novo multiple (>3) similarly affected unrelated individuals(PMID: 23791108, 25959749, 26714497, PS2_VS, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62, 3CNET: 0.822, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 8 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV003804262.1

#	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 Duke University Health System Sequencing Clinic, Duke University Health System, SCV003919073.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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, SCV004050492.1

#	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

Last Updated: Mar 30, 2024

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