Submissions for variant NM_015909.4(NBAS):c.1A>T (p.Met1Leu)

dbSNP: rs368516200

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	RCV002266488	SCV002547486	likely pathogenic	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: NBAS c.1A>T (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met162) is located in the encoded protein. Activation of the potential downstream translation initiation site would result in a shortened protein missing the first 161 amino acids from the protein sequence. Other pathogenic variants have been reported upstream of this alternate codon (e.g. c.17C>A, p.Ser6Ter; c.248_249dupTG, p.Val84TrpfsX6; c.405G>A, p.W135X; ClinVar and HGMD). Two of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250342 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>T in individuals affected with Liver Failure Acute Infantile, Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, other variants affecting the initiation codon (e.g. c.1A>G, c.1A>C) have been cited in online databases as likely pathogenic and disease-associated (LOVD, HGMD) and have been reported in affected patient(s) (PMID: 32957979). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003718465	SCV004502495	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the NBAS mRNA. The next in-frame methionine is located at codon 162. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1696343). This variant disrupts a region of the NBAS protein in which other variant(s) (p.Arg137Trp) have been determined to be pathogenic (PMID: 26286438, 26578240). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.