NM_015713.5(RRM2B):c.662A>G (p.Asn221Ser) AND Mitochondrial DNA depletion syndrome 8a

Germline classification:: Likely pathogenic (2 submissions)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000680084.5

Allele description [Variation Report for NM_015713.5(RRM2B):c.662A>G (p.Asn221Ser)]

NM_015713.5(RRM2B):c.662A>G (p.Asn221Ser)

Gene:

RRM2B:ribonucleotide reductase regulatory TP53 inducible subunit M2B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q22.3

Genomic location:

Preferred name:

NM_015713.5(RRM2B):c.662A>G (p.Asn221Ser)

Other names:

p.N221S:AAT>AGT

HGVS:

NC_000008.11:g.102218836T>C
NG_016617.1:g.25283A>G
NM_001172477.1:c.878A>G
NM_001172478.2:c.506A>G
NM_015713.5:c.662A>GMANE SELECT
NP_001165948.1:p.Asn293Ser
NP_001165949.1:p.Asn169Ser
NP_056528.2:p.Asn221Ser
NP_056528.2:p.Asn221Ser
LRG_788t1:c.878A>G
LRG_788t2:c.662A>G
LRG_788:g.25283A>G
LRG_788p1:p.Asn293Ser
LRG_788p2:p.Asn221Ser
NC_000008.10:g.103231064T>C
NM_015713.4:c.662A>G

Protein change:

N169S; ASN221SER

Links:

OMIM: 604712.0015; dbSNP: rs863224193

NCBI 1000 Genomes Browser:

rs863224193

Molecular consequence:

NM_001172477.1:c.878A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001172478.2:c.506A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015713.5:c.662A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mitochondrial DNA depletion syndrome 8a (MTDPS8A)
Synonyms:: MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY); MITOCHONDRIAL DNA DEPLETION SYNDROME, ENCEPHALOMYOPATHIC, WITH RENAL TUBULOPATHY, AUTOSOMAL RECESSIVE; Mitochondrial DNA depletion syndrome, encephalomyopathic form, with renal tubulopathy
Identifiers:: MONDO: MONDO:0012792; MedGen: C2749861; OMIM: 612075

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000807524	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 25326635
SCV001451966	OMIM	no assertion criteria provided	Pathogenic (Dec 29, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000807524

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001451966

OMIM

no assertion criteria provided

Pathogenic
(Dec 29, 2020)

germline

literature only

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	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

Molecular findings among patients referred for clinical whole-exome sequencing.

Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, et al.

JAMA. 2014 Nov 12;312(18):1870-9. doi: 10.1001/jama.2014.14601.

PubMed [citation]

PMID:: 25326635
PMCID:: PMC4326249

See all PubMed Citations (3)

Details of each submission

From Baylor Genetics, SCV000807524.3

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

#	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 OMIM, SCV001451966.1

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

Description

In a male infant, born to consanguineous Latino parents, with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), Penque et al. (2019) identified homozygosity for a c.662A-G transition (c.662A-G, NM_015713) in the RRM2B gene, resulting in an asn221-to-ser (N221S) substitution at a conserved residue in a highly conserved alpha helix region close to 2 known iron-binding sites. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present in 1 of 250,000 alleles in the gnomAD database. Molecular modeling suggested that the mutation disrupts the conserved alpha helix region by altering intramolecular interactions.

#	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

Last Updated: Nov 18, 2024

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