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

dbSNP: rs863224193

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196496	SCV000252199	likely pathogenic	not provided	2015-05-18	criteria provided, single submitter	clinical testing	p.Asn221Ser (AAT>AGT):c.662 A>G in exon 6 of the RRM2B gene (NM_015713.4). The N221S missense change in the RRM2B gene is likely disease-causing. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is conservative in that both Asparagine and Serine are uncharged, polar amino acids; however, this change occurs at a highly conserved position in the RRM2B protein, and other missense mutations at neighboring positions (I224S, G229V) have been reported in association with mitochondrial DNA depletion syndrome. Furthermore, multiple in-silico analysis models predict that N221S is damaging to the RRM2B protein. Therefore, N221S is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. Mutations in the RRM2B gene are associated with the autosomal recessive condition, mitochondrial DNA depletion syndrome 8A (MTDPS8A) and with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 5 (PEOA5). Autosomal dominant disease-causing mutations are typically associated with adult-onset of symptoms. The variant is found in MITONUC-MITOP panel(s).
Baylor Genetics	RCV000680084	SCV000807524	likely pathogenic	Mitochondrial DNA depletion syndrome 8a		criteria provided, single submitter	clinical testing
Pediatric Genomics Discovery Program, Yale University	RCV000714482	SCV000844949	uncertain significance	Severe lactic acidosis	2017-07-13	criteria provided, single submitter	research	We identified a homozygous p.Asn221Ser variant in RRM2B in an infant who developed hypotonia, failure to thrive, sensorineural hearing loss, and severe metabolic lactic acidosis, ultimately progressing to death at 3 months of age. Tissue studies to confirm the diagnosis of mitochondrial depletion were unable to be performed. Through molecular modeling using the X-ray crystal structure of p53R2, this variant likely causes disruption of a highly conserved helix region of the protein by altering intramolecular interactions (Smith et al. 2009; Scrutton and Raine 1996; Burley and Petsko 1986; Mitchell et al. 1994). Using ACMG 2015 Classification guidelines, this variant falls within VUS classification; however, there are now two unrelated homozygous patients (including this patient) reported with apparently similar presentations in ClinVar. This variant has been reported twice in ClinVar previously: once by Baylor Miraca Genetics Laboratory (SCV000807524.1) and once by GeneDx (SCV000252199.13). The patient described in SCV000807524.1 was 4 mo old and had renal tubular acidosis and congenital glaucoma, as well as a phenotype overlapping the patient described in this submission; this patient was also homozygous. The diagnosis Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) was associated with SCV000807524.1. No clinical information was provided for SCV000252199.13.
OMIM	RCV000680084	SCV001451966	pathogenic	Mitochondrial DNA depletion syndrome 8a	2020-12-29	no assertion criteria provided	literature only