Submissions for variant NM_001139.3(ALOX12B):c.1272dup (p.Lys425fs)

gnomAD frequency: 0.00004  dbSNP: rs763328506

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262748	SCV001440730	pathogenic	Autosomal recessive congenital ichthyosis 2	2020-09-04	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_001139.2:c.1144A>G.
GeneDx	RCV001838469	SCV002098162	pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Frameshift 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31168818, 19131948, 23083690, 33435499)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001838469	SCV002246447	pathogenic	not provided	2022-07-16	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 982978). This sequence change creates a premature translational stop signal (p.Lys425Glnfs*24) in the ALOX12B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALOX12B are known to be pathogenic (PMID: 16116617, 23621129, 31046801). This variant is present in population databases (rs763328506, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with congenital ichthyosis (PMID: 19131948, 23083690, 31168818). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226454	SCV003922788	pathogenic	Lamellar ichthyosis	2023-03-09	criteria provided, single submitter	clinical testing	Variant summary: ALOX12B c.1272dupC (p.Lys425GlnfsX24) 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 in ClinVar and are reported in association with autosomal recessive ichthyosis in HGMD. The variant allele was found at a frequency of 1.6e-05 in 248932 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1272dupC has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis (e.g., Eckl_2009, Osorio_2013, Hotz_2021). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001262748	SCV005652823	pathogenic	Autosomal recessive congenital ichthyosis 2	2024-03-21	criteria provided, single submitter	clinical testing
Institute for Human Genetics, University Medical Center Freiburg	RCV001262748	SCV001477407	pathogenic	Autosomal recessive congenital ichthyosis 2	2021-01-07	no assertion criteria provided	clinical testing