Submissions for variant NM_015909.4(NBAS):c.686dup (p.Ser230fs)

dbSNP: rs759315662

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487069	SCV000566829	pathogenic	not provided	2017-09-13	criteria provided, single submitter	clinical testing	The c.686dupT pathogenic variant in the NBAS gene has been reported previously in combination with another NBAS variant in at least two individuals with features of NBAS-related disorder, including early onset recurrent acute liver failure and short stature (Haack et al., 2015; Staufner et al., 2016). The c.686dupT variant causes a frameshift starting with codon Serine 230, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Ser230GlnfsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.686dupT variant is observed in 10/6,614 (0.15%) alleles from individuals of Finnish background in the ExAC dataset (Lek et al., 2016). We interpret c.686dupT as a pathogenic variant.
Invitae	RCV000487069	SCV002241841	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser230Glnfs*4) in the NBAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBAS are known to be pathogenic (PMID: 26073778, 26541327, 27789416, 28031453). This variant is present in population databases (rs759315662, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with clinical features of SPOH syndrome (PMID: 26073778). ClinVar contains an entry for this variant (Variation ID: 204581). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000487069	SCV002498523	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469052	SCV002766389	pathogenic	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2022-11-05	criteria provided, single submitter	clinical testing	Variant summary: NBAS c.686dupT (p.Ser230GlnfsX4) 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. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.1213C>T [p.Arg405Ter], c.1987C>T [p.Gln663Ter]). The variant allele was found at a frequency of 0.00041 in 282794 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBAS causing Liver Failure Acute Infantile, Type 2 (0.00041 vs 0.0011), allowing no conclusion about variant significance. c.686dupT has been reported in the literature as a biallelic genotype in individuals affected with Recurrant Acute Liver Failture (e.g. Haack_2015, Baldridge_2017, Carli_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003947561	SCV004775129	pathogenic	NBAS-related condition	2023-12-11	criteria provided, single submitter	clinical testing	The NBAS c.686dupT variant is predicted to result in a frameshift and premature protein termination (p.Ser230Glnfs*4). This variant has been reported in the compound heterozygous state in two unrelated individuals with acute liver failure (Families 1 and 10, Haack et al. 2015. PubMed ID: 26073778), and a third individual with hepatic, skeletal, ocular, and immunologic features, as well as dysmorphic facies (Patient 2, Carli et al. 2019. PubMed ID: 30825388). This variant is reported in 0.12% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in NBAS are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000186578	SCV000240154	pathogenic	Infantile liver failure syndrome 2	2015-07-02	no assertion criteria provided	literature only
Laboratory of Medical Genetics, University of Torino	RCV000186578	SCV000882688	pathogenic	Infantile liver failure syndrome 2	2018-11-07	no assertion criteria provided	clinical testing	Found in compound heterozygosity with c.6840G>A