NM_001111.5(ADAR):c.577C>G (p.Pro193Ala) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Nov 4, 2024
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:: RCV000255775.46

Allele description [Variation Report for NM_001111.5(ADAR):c.577C>G (p.Pro193Ala)]

NM_001111.5(ADAR):c.577C>G (p.Pro193Ala)

Gene:

ADAR:adenosine deaminase RNA specific [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.3

Genomic location:

Preferred name:

NM_001111.5(ADAR):c.577C>G (p.Pro193Ala)

HGVS:

NC_000001.11:g.154602065G>C
NG_011844.2:g.34496C>G
NM_001025107.3:c.-309C>G
NM_001111.5:c.577C>GMANE SELECT
NM_001193495.2:c.-309C>G
NM_001365045.1:c.604C>G
NM_001365046.1:c.-309C>G
NM_001365047.1:c.-309C>G
NM_001365048.1:c.-309C>G
NM_001365049.1:c.-309C>G
NM_015840.4:c.577C>G
NM_015841.4:c.577C>G
NP_001102.3:p.Pro193Ala
NP_001351974.1:p.Pro202Ala
NP_056655.3:p.Pro193Ala
NP_056656.3:p.Pro193Ala
LRG_1212t1:c.577C>G
LRG_1212:g.34496C>G
LRG_1212p1:p.Pro193Ala
NC_000001.10:g.154574541G>C
NG_011844.1:g.30897C>G
NM_001111.4:c.577C>G
NP_001102.2:p.Pro193Ala
P55265:p.Pro193Ala

Protein change:

P193A; PRO193ALA

Links:

UniProtKB: P55265#VAR_069535; OMIM: 146920.0007; dbSNP: rs145588689

NCBI 1000 Genomes Browser:

rs145588689

Molecular consequence:

NM_001025107.3:c.-309C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001193495.2:c.-309C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001365046.1:c.-309C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001365047.1:c.-309C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001365048.1:c.-309C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001365049.1:c.-309C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001111.5:c.577C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365045.1:c.604C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015840.4:c.577C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015841.4:c.577C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321382	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 4, 2024)	germline	clinical testing	Citation Link,
SCV000332712	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 18, 2015)	germline	clinical testing	Citation Link,
SCV001247918	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2024)	germline	clinical testing	Citation Link,
SCV001447200	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002021311	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002064425	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 6, 2019)	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	germline	yes	6	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	8	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000321382.13

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

Description

Conflicting evidence has been reported regarding the effect of this variant on protein function and structure (PMID: 25456137, 29603717); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33289110, 35960392, 37541188, 27539236, 29030706, 31692161, 24262145, 27290639, 28139822, 23001123, 29221912, 29603717, 30609409, 31664448, 31737037, 30729177, 31772029, 31980526, 34758253, 27943079, 34426522, 33307271, 34778129, 34631961, Liang[article]2022, 38292175, 35859177, 25456137, 37421629, 33528536)

#	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 Eurofins Ntd Llc (ga), SCV000332712.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	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		8	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001247918.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

Description

ADAR: PM3:Strong, PM2, PM5, PS3:Moderate

#	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		6	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447200.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002021311.3

#	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 Genetic Services Laboratory, University of Chicago, SCV002064425.1

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

Description

DNA sequence analysis of the ADAR gene demonstrated a sequence change, c.577C>G, in exon 2 that results in an amino acid change, p.Pro193Ala. The p.Pro193Ala change affects a moderately conserved amino acid residue located in a domain of the ADAR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro193Ala substitution. The variant has been reported previously in the compound heterozygous state with another ADAR pathogenic variant in several individuals with Aicardi-Goutieres syndrome (Rice et al., 2012). Functional studies in HEK293 cells transfected with the p.Pro193Ala variant exhibit a significant decrease in RNA-editing enzyme activity (Mannion et al., 2014). This sequence change has been described in the gnomAD database with a population frequency of 0.21% (dbSNP rs145588689). We classify this sequence change as likely 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

Last Updated: Nov 24, 2024

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