Submissions for variant NM_004341.5(CAD):c.5429G>A (p.Arg1810Gln)

gnomAD frequency: 0.00028  dbSNP: rs139332887

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485191	SCV000571629	likely pathogenic	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Has been reported in patients with CAD deficiency in the published literature (PMID: 32820246, 33497533, 37540500); Published functional studies suggest a damaging effect with this variant possibly resulting in decreased protein stability (PMID: 37540500); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32820246, 35242569, 28719003, 26740555, 37540500, Dragolova2022[BachelorsThesis], 33497533)
Mendelics	RCV000986606	SCV001135642	likely pathogenic	Developmental and epileptic encephalopathy, 50	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778976	SCV002014904	likely pathogenic	Infantile epileptic dyskinetic encephalopathy	2021-10-14	criteria provided, single submitter	clinical testing	Variant summary: CAD c.5429G>A (p.Arg1810Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 235756 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CAD causing Early Infantile Epileptic Encephalopathy, 50 (0.00034 vs 0.0011), allowing no conclusion about variant significance. c.5429G>A has been reported in the literature in individuals affected with CAD deficiency (Rymen_2020, McGraw_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000485191	SCV002147772	pathogenic	not provided	2024-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1810 of the CAD protein (p.Arg1810Gln). This variant is present in population databases (rs139332887, gnomAD 0.2%). This missense change has been observed in individual(s) with CAD-related conditions (PMID: 32820246, 33497533). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 422220). 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. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000986606	SCV004238519	likely pathogenic	Developmental and epileptic encephalopathy, 50	2023-07-21	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000986606	SCV005086422	likely pathogenic	Developmental and epileptic encephalopathy, 50	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 50 (MIM#616457). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (94 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 1 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified several times as likely pathogenic, and reported in at least five unrelated individuals with uridine-responsive epileptic encephalopathy (ClinVar, PMID: 33497533, PMID: 32820246). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated in two affected siblings, however there is insufficent segregation evidence to establish the significance of this finding (PMID: 33497533). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000986606	SCV005655942	likely pathogenic	Developmental and epileptic encephalopathy, 50	2024-06-19	criteria provided, single submitter	clinical testing