Submissions for variant NM_173076.3(ABCA12):c.6234-1G>C

dbSNP: rs1553520468

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000578204	SCV000680019	pathogenic	Autosomal recessive congenital ichthyosis 4B	2022-06-24	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 harlequin ichthyosis 4B (MIM#242500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies using patient EBV-transformed lymphoblasts demonstrated out-of-frame skipping of exon 43 which resulted in a frameshift and subsequent nonsense-mediated decay of the resulting protein (Splicing Diagnostics, Kids Neuroscience Centre). (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are multiple likely pathogenic or pathogenic NMD-predicted variants that have been previously reported (DECIPHER). (SP) 0807 - This variant has no previous evidence of pathogenicity. However, it should be noted that the proband of this family has been reported by VCGS and our collaborators (ClinVar, PMID: 29543227). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Kids Neuroscience Centre, Sydney Children's Hospitals Network	RCV000578204	SCV001571509	pathogenic	Autosomal recessive congenital ichthyosis 4B		criteria provided, single submitter	clinical testing	The c.6234-1G>C variant induces exon 43 skipping (p.Tyr2079Leufs*2) causing a frameshift, encoding a missense amino acid and a premature termination codon. These transcripts are targeted for nonsense-mediated decay. Mis-spliced ABCA12 transcripts with exon 43 skipping that escape nonsense-mediated decay encode ABCA12 proteins missing 516 amino acids from the C-terminus p.(Tyr2079_Ser2595del), including the entire C-terminal ABC transporter domain.