Submissions for variant NM_173076.3(ABCA12):c.1222T>C (p.Ser408Pro)

gnomAD frequency: 0.00022  dbSNP: rs189141015

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000762318	SCV000892623	likely benign	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV000762318	SCV001122329	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001137305	SCV001297231	likely benign	Congenital ichthyosis of skin	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
PreventionGenetics, part of Exact Sciences	RCV003918248	SCV004737189	likely benign	ABCA12-related disorder	2019-03-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000762318	SCV001554029	likely benign	not provided		no assertion criteria provided	clinical testing	The ABCA12 p.Ser408Pro variant was not identified in the literature but was identified in dbSNP (ID: rs189141015) and ClinVar (classification not provided). The variant was identified in control databases in 323 of 282404 chromosomes (3 homozygous) at a frequency of 0.001144 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 263 of 30604 chromosomes (freq: 0.008594), Other in 4 of 7208 chromosomes (freq: 0.000555), European (non-Finnish) in 44 of 129014 chromosomes (freq: 0.000341), Latino in 10 of 35404 chromosomes (freq: 0.000283), Ashkenazi Jewish in 1 of 10366 chromosomes (freq: 0.000096) and African in 1 of 24886 chromosomes (freq: 0.00004), but was not observed in the East Asian or European (Finnish) populations. The p.Ser408 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.