Submissions for variant NM_173076.3(ABCA12):c.2033A>G (p.Asn678Ser)

gnomAD frequency: 0.00138  dbSNP: rs147218173

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000345632	SCV000427298	uncertain significance	Congenital ichthyosis of skin	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV002487485	SCV002780163	uncertain significance	Autosomal recessive congenital ichthyosis 4A; Autosomal recessive congenital ichthyosis 4B	2021-12-14	criteria provided, single submitter	clinical testing
Invitae	RCV001358602	SCV003275195	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155165	SCV003844958	likely benign	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: ABCA12 c.2033A>G (p.Asn678Ser) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251360 control chromosomes. The observed variant frequency is approximately 1.63 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA12 causing Lamellar Ichthyosis phenotype (0.00066), suggesting that the variant is benign. c.2033A>G has been reported in the literature in individuals affected with Lamellar Ichthyosis and Posterior Segment Uveitis, without strong evidence for causality (Scott_2013, Li_2021). These reports do not provide unequivocal conclusions about association of the variant with Lamellar Ichthyosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as VUS while one classified as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Breakthrough Genomics, Breakthrough Genomics	RCV001358602	SCV005188267	uncertain significance	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358602	SCV001554388	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ABCA12 p.Asn678Ser variant was identified in 1 of 28 proband chromosomes (frequency: 0.0357) in the compound heterozygous state from an individual with inherited ichthyoses (Scott_2013_PMID:22992804). The variant was identified in dbSNP (ID: rs147218173) and ClinVar (classified as VUS by Illumina for congenital ichthyosis) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 305 of 282714 chromosomes at a frequency of 0.001079 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 256 of 129058 chromosomes (freq: 0.001984), Other in 14 of 7216 chromosomes (freq: 0.00194), Latino in 25 of 35434 chromosomes (freq: 0.000706), African in 8 of 24954 chromosomes (freq: 0.000321) and European (Finnish) in 2 of 25120 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Asn678 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.