Submissions for variant NM_023936.2(MRPS34):c.94C>T (p.Gln32Ter)

gnomAD frequency: 0.00071  dbSNP: rs763672163

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000505531	SCV000787467	likely pathogenic	Combined oxidative phosphorylation deficiency 32	2018-04-16	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Combined oxidative phosphorylation deficiency 32, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:28777931).
GeneDx	RCV000760555	SCV000890446	pathogenic	not provided	2023-09-16	criteria provided, single submitter	clinical testing	Nonsense 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; This variant is associated with the following publications: (PMID: 28777931, 30358850, 30566640, 35326425, 37385809)
CeGaT Center for Human Genetics Tuebingen	RCV000760555	SCV001149646	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000760555	SCV001208611	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln32*) in the MRPS34 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MRPS34 are known to be pathogenic (PMID: 28777931). This variant is present in population databases (rs763672163, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Leigh syndrome, transient metabolic acidosis and hemodynamic instability related to tubulopathy (PMID: 28777931). ClinVar contains an entry for this variant (Variation ID: 438635). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000505531	SCV001524838	pathogenic	Combined oxidative phosphorylation deficiency 32	2019-09-27	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID: 28777931, ClinVar ID: 438635]
Revvity Omics, Revvity	RCV000505531	SCV002023518	likely pathogenic	Combined oxidative phosphorylation deficiency 32	2023-01-12	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000505531	SCV002061558	likely pathogenic	Combined oxidative phosphorylation deficiency 32	2021-05-12	criteria provided, single submitter	clinical testing	PVS1, PM3
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000505531	SCV002320736	pathogenic	Combined oxidative phosphorylation deficiency 32	2022-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505531	SCV002572006	pathogenic	Combined oxidative phosphorylation deficiency 32	2024-03-06	criteria provided, single submitter	clinical testing	Variant summary: MRPS34 c.94C>T (p.Gln32X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00044 in 52648 control chromosomes (gnomAD). c.94C>T has been reported in the literature in individuals affected with Combined Oxidative Phosphorylation Deficiency 32 or Leigh syndrome (Lake_2017, Shen_2023). Western blot analysis using fibroblasts from one patient showed a significant reduction in the MRPS34 protein, as well as reduction in complexes CI and CIV (Lake_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28777931, 35326425, 37385809). ClinVar contains an entry for this variant (Variation ID: 438635). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000505531	SCV002767779	pathogenic	Combined oxidative phosphorylation deficiency 32	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. 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 32 (MIM#61766). (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 v3 <0.01 for a recessive condition (100 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable NMD-predicted variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic or likely pathogenic (ClinVar, LOVD) and has been reported in a single compound heterozygous patient with Leigh's syndrome (PMID: 28777931). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies on patient cells found this variant resulted in reduced OXPHOS levels, mitochondrial protein translation and mitochondrial subunit proteins. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525951	SCV005040179	pathogenic	Ataxia-telangiectasia syndrome	2024-03-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.94C>T (p.Arg32Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage (IPR021668) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251158 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.8e-05 vs 0.004), allowing no conclusion about variant significance. c.94C>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia. These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 142913). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000760555	SCV005199168	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000505531	SCV000599787	pathogenic	Combined oxidative phosphorylation deficiency 32	2017-09-15	no assertion criteria provided	literature only