ClinVar Miner

Submissions for variant NM_002936.6(RNASEH1):c.424G>A (p.Val142Ile)

gnomAD frequency: 0.00001  dbSNP: rs766294940
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000412621 SCV001571366 likely pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 2021-04-12 criteria provided, single submitter clinical testing
GeneDx RCV001566031 SCV001789496 pathogenic not provided 2019-12-18 criteria provided, single submitter clinical testing Published functional studies demonstrate that the V142I variant damages the mitochondria and significantly impairs the function of RNASEH1 with approximately 60% decreased activity compared to wild-type (Akman et al., 2016; Reyes et al., 2015); This variant is associated with the following publications: (PMID: 31271879, 31178343, 30340744, 26094573, 28508084, 27402764, 26968897)
Invitae RCV001566031 SCV003513009 pathogenic not provided 2022-04-06 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 142 of the RNASEH1 protein (p.Val142Ile). This variant is present in population databases (rs766294940, gnomAD 0.02%). This missense change has been observed in individuals with chronic progressive external ophthalmoplegia with mitochondrial DNA deletions (PMID: 26094573, 28508084). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372197). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000412621 SCV004100450 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 criteria provided, single submitter clinical testing The missense variant p.V142I in RNASEH1 (NM_002936.6) has been previously reported in affected indviduals. Functional studies reveal a damaging effect (Reyes et al,2016). The variant has been submitted to ClinVar as Pathogenic. The p.V142I variant is observed in 6/34,588 (0.0173%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.V142I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 142 of RNASEH1 is conserved in all mammalian species. The nucleotide c.424 in RNASEH1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000412621 SCV000490270 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 2015-07-29 no assertion criteria provided literature only

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