Submissions for variant NM_173076.3(ABCA12):c.4139A>G (p.Asn1380Ser)

gnomAD frequency: 0.00004  dbSNP: rs28940269

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255645	SCV000321322	pathogenic	not provided	2023-04-09	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: 20672373, 29630152, 27025581, 29722424, 30530421, 10094194, 8845852, 21729033, 12915478, 31168818, 32851342, 30916489, 29887490, 32069299, 36980989)
Fulgent Genetics, Fulgent Genetics	RCV000763068	SCV000893574	likely pathogenic	Autosomal recessive congenital ichthyosis 4A; Autosomal recessive congenital ichthyosis 4B	2022-05-14	criteria provided, single submitter	clinical testing
3billion	RCV000002989	SCV002521606	pathogenic	Autosomal recessive congenital ichthyosis 4A	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.82). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002855). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:29722424, 30916489). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 29722424, 29887490, 30916489). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000002989	SCV002557620	pathogenic	Autosomal recessive congenital ichthyosis 4A	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital ichthyosis 4A (MIM#601277) and congenital ichthyosis 4B (harlequin) (MIM#242500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transporter 1 domain (Decipher). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in compound heterozygous and homozygous states in multiple individuals with congenital ichthyosis (ClinVar, PMID: 30916489, 32851342). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255645	SCV004264705	pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1380 of the ABCA12 protein (p.Asn1380Ser). This variant is present in population databases (rs28940269, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital ichthyosis (PMID: 12915478, 31168818, 32851342). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2855). 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) performed at Invitae indicates that this missense variant is expected to disrupt ABCA12 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000002989	SCV000023147	pathogenic	Autosomal recessive congenital ichthyosis 4A	2003-09-15	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255645	SCV001951563	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255645	SCV001966105	likely pathogenic	not provided		no assertion criteria provided	clinical testing