NM_024570.4(RNASEH2B):c.2T>C (p.Met1Thr) AND Aicardi-Goutieres syndrome 2

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 1, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000819510.12

Allele description [Variation Report for NM_024570.4(RNASEH2B):c.2T>C (p.Met1Thr)]

NM_024570.4(RNASEH2B):c.2T>C (p.Met1Thr)

Genes:

LOC130009810:ATAC-STARR-seq lymphoblastoid silent region 5362 [Gene]
RNASEH2B-AS1:RNASEH2B antisense RNA 1 [Gene - HGNC]
RNASEH2B:ribonuclease H2 subunit B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.3

Genomic location:

Preferred name:

NM_024570.4(RNASEH2B):c.2T>C (p.Met1Thr)

HGVS:

NC_000013.11:g.50910078T>C
NG_009055.1:g.5323T>C
NM_001142279.2:c.2T>C
NM_024570.4:c.2T>CMANE SELECT
NP_001135751.1:p.Met1Thr
NP_078846.2:p.Met1Thr
NP_078846.2:p.Met1Thr
LRG_279t1:c.2T>C
LRG_279t2:c.2T>C
LRG_279:g.5323T>C
LRG_279p1:p.Met1Thr
LRG_279p2:p.Met1Thr
NC_000013.10:g.51484214T>C
NM_024570.3:c.2T>C

Protein change:

M1T

Links:

dbSNP: rs1457494794

NCBI 1000 Genomes Browser:

rs1457494794

Molecular consequence:

NM_001142279.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_024570.4:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001142279.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024570.4:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Aicardi-Goutieres syndrome 2
Identifiers:: MONDO: MONDO:0012429; MedGen: C3489724; Orphanet: 51; OMIM: 610181

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000960174	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001251493	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000960174

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 1, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001251493

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

research

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000960174.6

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

Description

This sequence change affects the initiator methionine of the RNASEH2B mRNA. The next in-frame methionine is located at codon 31. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. Disruption of the initiator codon has been observed in individual(s) with clinical features of RNASEH2B-related conditions (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251493.2

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

Description

The RNASEH2B c.2T>C (p.M1T) variant is predicted to result in the loss of a start codon corresponding to the first amino acid of the RNASEH2B protein, which may lead to an aberrant protein.

#	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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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