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Mitochondrial DNA (mtDNA) variant pathogenicity interpretation has special considerations given unique features of the mtDNA genome, including maternal inheritance, variant heteroplasmy, threshold effect, absence of splicing, and contextual effects of haplogroups. Currently there are insufficient standardized criteria for mtDNA variant assessment, which leads to inconsistencies in clinical variant pathogenicity reporting. An international working group of mtDNA experts was assembled within the Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium and obtained Expert Panel status from ClinGen. This group reviewed the 2015 American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) standards and guidelines that are widely used for clinical interpretation of DNA sequence variants and provided further specifications for additional and specific guidance related to mtDNA variant classification. These Expert Panel based consensus specifications allow for consistent consideration of the unique aspects of the mtDNA genome that directly influence variant assessment, including addressing mtDNA genome composition and structure, haplogroups and phylogeny, maternal inheritance, heteroplasmy, and functional analyses unique to mtDNA, as well specifications for utilization of mtDNA genomic databases and computational algorithms.

The dramatic advances in genetic sequencing technologies used in research laboratories are now entering the clinic, and applications of whole-genome and whole-exome sequencing to disease diagnosis, predisposition, and treatment will soon be commonplace. However, the standards and methods for identifying clinically relevant variants are currently being debated and defined. Multiple agencies worldwide have recognized that we have reached an exciting and critical transition point into the clinic, and many important issues are being discussed that impact how genetic variation data in the clinic will be interpreted and used. The 2013 annual scientific meeting of the Human Genome Variation Society (HGVS) had as its main theme the discovery, interpretation, and dissemination of clinically relevant DNA variants. The meeting featured the continuously developing technology of databasing genetic variation and computational tools for allelic variant discovery. Attention was given to curating and integrating these data with clinical findings, including approaches to distinguish between functional alleles underlying clinical phenotypes and benign sequence variants and making data sources interoperable and functional for clinical diagnostic utility, citing examples in specific diseases.

Biotinidase (BTD) is the only enzyme that can cleave biocytin, a product of the proteolytic digestion of holocarboxylases. Profound BTD deficiency (less than 10% mean normal activity in serum) is an autosomal recessive disorder that can result in neurological and cutaneous abnormalities. Both the cDNA and the genomic DNA of normal BTD gene have been isolated and characterized. The BTD gene is localized to chromosome 3p25. Thus far 61 mutations in three of the four exons of the BTD and one mutation in an intron gene that cause profound BTD deficiency have been reported. Mutations occur at different frequencies in symptomatic children than they do in children ascertained by newborn screening. Two mutations, 98-104del7ins3 and R538C, were present in 52% or 31 of 60 alleles found in symptomatic patients. Three other mutations, A755G, Q456H, and 511 G>A; 1330G>C (double mutation), accounted for 52% of the alleles detected by newborn screening in the United States. Two asymptomatic adults, parents of children with profound BTD deficiency detected by newborn screening, have been described. Additional different mutations have been found in Turkish, Saudi Arabian, and Japanese children with profound BTD deficiency. Partial BTD deficiency (10–30% of mean normal serum activity) is predominantly caused by the single 1330G>C mutation that results in D444H on one allele in combination with one of the mutations causing profound deficiency on the other allele. Four intragenic polymorphisms, three neutral and one amino acid change, have also been found. Although a preponderance of mutations causing the production of truncated BTD protein occurs in symptomatic children with profound deficiency, preliminary studies fail to demonstrate clear genotype–phenotype correlations. Hum Mutat 18:375–381, 2001. © 2001 Wiley-Liss, Inc.