Submissions for variant NM_000350.3(ABCA4):c.4070C>A (p.Ala1357Glu)

dbSNP: rs552517556

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000761667	SCV000891840	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000761667	SCV001380735	pathogenic	not provided	2021-07-21	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 623693). This variant has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 23982839; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 1357 of the ABCA4 protein (p.Ala1357Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala1357 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22229821, 23755871, 29847635). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800573	SCV005422558	pathogenic	Retinitis pigmentosa	2024-10-22	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.4070C>A (p.Ala1357Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250020 control chromosomes (gnomAD). c.4070C>A has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa (Fujinami_2013, Sung_2020, Chen_2021, Cornelis_2022, Li_2022). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.4070C>T, p.Ala1357Val), supporting the critical relevance of codon 1357 to ABCA4 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23982839, 33608557, 35120629, 38219857, 33261146). ClinVar contains an entry for this variant (Variation ID: 623693). Based on the evidence outlined above, the variant was classified as pathogenic.
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV004564474	SCV005047009	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research