ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The ABCA4 c.455G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: BS1, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.

This variant is associated with the following publications: (PMID: 11702214, 23143460, 22264887, 11385708, 26593885, 14517951, 15192030, 25444351, 28118664, 22328824, 15161829, 10958763, 23953153, 16917483, 26764160, 28898540, 29925512, 30093795, 31456290)

ABCA4: BP4, BS2

The ABCA4 p.Arg152Gln variant was identified in 5 of 958 proband chromosomes (frequency: 0.005) from individuals or families with Stargardt Disease and Age-related Macular Degeneration and was present in 3 of 440 control chromosomes (frequency: 0.0068) from healthy individuals (Rivera_2000_PMID:10958763; Schulz_2017_PMID:28118664). The variant was also identified in dbSNP (ID: rs62646862), LOVD 3.0 and in ClinVar (classified as likely benign by EGL Genetics, GeneDx and ARUP Laboratories and as likely pathogenic by the University Regensberg Institute of Human Genetics). The variant was not identified in Cosmic. The variant was identified in control databases in 651 of 251232 chromosomes (2 homozygous) at a frequency of 0.002591 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 420 of 113574 chromosomes (freq: 0.003698), South Asian in 96 of 30610 chromosomes (freq: 0.003136), Other in 18 of 6136 chromosomes (freq: 0.002934), Latino in 86 of 34578 chromosomes (freq: 0.002487), African in 14 of 16230 chromosomes (freq: 0.000863) and European (Finnish) in 17 of 21646 chromosomes (freq: 0.000785); it was not observed in the Ashkenazi Jewish and East Asian populations. The p.Arg152 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) 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.

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).

Variant interpretted as Uncertain significance and reported on 06-25-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.