ClinVar Miner

Submissions for variant NM_001083614.2(EARS2):c.212del (p.Phe71fs)

dbSNP: rs778413603
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487247 SCV000566972 likely pathogenic not provided 2024-01-16 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published in association with an EARS-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 31980526)
Genetics and Molecular Pathology, SA Pathology RCV003447531 SCV004175246 pathogenic Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome 2022-12-19 criteria provided, single submitter clinical testing The EARS2 c.212del variant is classified as Pathogenic (PVS1, PM2, PM3_supporting) This EARS2 c.212del variant is located in exon 2/9 and is predicted to cause a shift in the reading frame at codon 71, likely resulting in non-sense mediated decay of the protein product (PVS1). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152212 sequenced alleles) (PM2). This variant has been detected in trans with a likely pathogenic variant (c.320G>A) for this recessive condition (PM3_supporting). The variant has been reported in dbSNP (rs778413603) and has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 419276). It has not been reported in HGMD.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV003447531 SCV005086788 pathogenic Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome 2023-07-17 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 12 (MIM#614924). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as likely pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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