ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1267_1268inv (p.His423Cys)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001211455 SCV001382996 uncertain significance not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 423 of the ABCA4 protein (p.His423Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ABCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 941627). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002471046 SCV002766672 uncertain significance Stargardt disease 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ABCA4-related eye disease (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to cysteine. This is likely due to an inversion event of two nucleotides. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (30 individuals). This zygosity of these individuals (heterozygous or homozygous) is unknown. (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (52722 heterozygotes, 9821 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by two in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0709 - Another missense variant comparable to the one identified in this case has strong previous evidence for being benign. This alternative change (p.His423Arg) has been reported many times as likely benign and benign. Other alternative changes (p.His423Tyr, p.His423Pro) have also been observed, and have been reported as VUS (ClinVar, LOVD). (SB) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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