Submissions for variant NM_001195518.2(MICU1):c.355C>T (p.Arg119Ter)

dbSNP: rs538329212

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498673	SCV000589496	pathogenic	not provided	2022-03-08	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; Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498673	SCV002243867	pathogenic	not provided	2023-08-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 431921). This variant has not been reported in the literature in individuals affected with MICU1-related conditions. This variant is present in population databases (rs538329212, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg119*) in the MICU1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MICU1 are known to be pathogenic (PMID: 24336167).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004579549	SCV005062117	pathogenic	Proximal myopathy with extrapyramidal signs	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: CBARA1 c.355C>T (p.Arg119X) 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 8.1e-06 in 246226 control chromosomes. To our knowledge, no occurrence of c.355C>T in individuals affected with Proximal Myopathy With Extrapyramidal Signs and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 431921). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004579549	SCV005087001	pathogenic	Proximal myopathy with extrapyramidal signs	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. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with myopathy with extrapyramidal signs (MIM#615673). (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) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by two clinical laboratories 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) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign