Submissions for variant NM_001139.3(ALOX12B):c.1579G>A (p.Val527Met)

gnomAD frequency: 0.00006  dbSNP: rs199545653

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421593	SCV000521132	likely pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27025581, 17139268, 19890349, 26762237, 34426522, 31168818, 35315045, 33435499)
SIB Swiss Institute of Bioinformatics	RCV000193750	SCV000803495	likely pathogenic	Autosomal recessive congenital ichthyosis 2	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Ichthyosis, congenital, autosomal recessive 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => found in unrelated patients (PMID:26762237) (PMID:17139268) (PMID:19890349). PM3 => For recessive disorders, detected in trans with a likely pathogenic variant (PMID:26762237).
Invitae	RCV000421593	SCV002142346	pathogenic	not provided	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 527 of the ALOX12B protein (p.Val527Met). This variant is present in population databases (rs199545653, gnomAD 0.02%). This missense change has been observed in individuals with congenital ichthyosis (PMID: 17139268, 27025581). ClinVar contains an entry for this variant (Variation ID: 212729). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALOX12B protein function. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000421593	SCV005199517	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000193750	SCV000223920	likely pathogenic	Autosomal recessive congenital ichthyosis 2	2014-11-19	no assertion criteria provided	clinical testing
Institute for Human Genetics, University Medical Center Freiburg	RCV000193750	SCV001477962	pathogenic	Autosomal recessive congenital ichthyosis 2	2021-01-07	no assertion criteria provided	clinical testing