Submissions for variant NM_015909.4(NBAS):c.6877del (p.Leu2293fs)

dbSNP: rs761634052

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582344	SCV001821213	likely pathogenic	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2021-08-10	criteria provided, single submitter	clinical testing	Variant summary: NBAS c.6877delC (p.Leu2293CysfsX9) 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 7.2e-05 in 251436 control chromosomes, predominantly at a frequency of 0.00052 within the Latino subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in NBAS causing Liver Failure Acute Infantile, Type 2 (0.00052 vs 0.0011), allowing no conclusion about variant significance. c.6877delC has been reported in the literature in a compound heterozygous individual affected with NBAS-associated disease with clinical symptoms including acute infantile liver failure and multisystemic features (Staufner_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001866206	SCV002183803	uncertain significance	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2293Cysfs*9) in the NBAS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the NBAS protein. This variant is present in population databases (rs761634052, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with SOPH syndrome (PMID: 31761904). ClinVar contains an entry for this variant (Variation ID: 1217235). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the NBAS protein in which other variant(s) (p.Leu2348del) have been observed in individuals with NBAS-related conditions (PMID: 31216810, 32812336). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.