ClinVar Genomic variation as it relates to human health

DNA sequence analysis of the COASY gene demonstrated a two base pair duplication in exon 7, c.1403_1404dup. This sequence change results in the creation of a premature stop codon at amino acid position 469, p.Ile469*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated COASY protein with potentially abnormal function. This sequence change has not been previously described in patients with COSY--related neurodegeneration; however, other loss-of-function variants, including downstream of this variant, have been reported to be disease causing. Based on the above we interpret this variant as likely pathogenic.

This sequence change creates a premature translational stop signal (p.Ile469*) in the COASY gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COASY are known to be pathogenic (PMID: 24360804, 30089828). This variant is present in population databases (rs560987504, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with COASY-related conditions. ClinVar contains an entry for this variant (Variation ID: 421057). For these reasons, this variant has been classified as Pathogenic.

The c.1490_1491dupTG (p.I498*) alteration, located in exon 9 (coding exon 8) of the COASY gene, consists of a duplication of TG at position 1490, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the TGTG allele has an overall frequency of 0.05% (145/282266) total alleles studied. The highest observed frequency was 0.09% (116/128832) of European (non-Finnish) alleles. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with COASY protein-associated neurodegeneration (PMID: 24360804). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (145 heterozygotes, 0 homozygotes). (SP) 0703 - Other NMD variants comparable to the one identified in this case have moderate previous evidence for pathogenicity (ClinVar, Decipher, LOVD). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals with neurodegeneration with brain iron accumulation (ClinVar, LOVD). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 38750253, Lynch[poster]2021)

Variant summary: COASY c.1403_1404dupTG (p.Ile469X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00051 in 250902 control chromosomes, predominantly at a frequency of 0.0009 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.76 fold of the estimated maximal expected allele frequency for a pathogenic variant in COASY causing Neurodegeneration With Brain Iron Accumulation phenotype (0.00019). However, no homogzygotes were present in gnomad. c.1403_1404dupTG has been reported in the literature in compound heterozygous individuals affected with Neurodegeneration With Brain Iron Accumulation, including two affected siblings (Cavestro_2024). 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. The following publication have been ascertained in the context of this evaluation (PMID: 38750253). ClinVar contains an entry for this variant (Variation ID: 421057). Based on the evidence outlined above, the variant was classified as pathogenic.

The COASY c.1403_1404dupTG variant is predicted to result in premature protein termination (p.Ile469*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.090% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/421057). Nonsense variants in COASY are expected to be pathogenic and therefore we interpret c.1403_1404dup (p.Ile469*) as likely pathogenic.