ClinVar Miner

Submissions for variant NM_003937.3(KYNU):c.1045_1051del (p.Phe349fs) (rs770642379)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Embryology Laboratory,Victor Chang Cardiac Research Institute RCV000496114 SCV000540923 pathogenic Congenital NAD deficiency disorder 2016-12-23 criteria provided, single submitter research This variant was discovered in a North American family. The patient presented multiple congenital malformations affecting vertebrae, heart, kidney among others. This variant is a protein truncating variant and novel (ExAC MAF 0). The patient is compound heterzygous for this variant and another protein truncating variant in the same KYNU gene (NM_003937.2:c.468T>A). Her unaffected parents are heterzygous for only one variant. Enzyme assay confirmed that the protein product of this gene variant has lost enzyme activity. Mouse embryos homozygous null for Kynu presented similar phenotype as observed in the patient, and also showed reduced concentration of NAD in the embryonic tissue.
GeneDx RCV000520521 SCV000618083 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing The c.1045_1051delTTTAAGC variant in the KYNU gene identified in this individual has now been published as a possible disease-related variant associated with NAD deficiency (Shi et al., 2017). To our knowledge, this individual represents the only reported individual to harbor this variant. The c.1045_1051delTTTAAGC variant causes a frameshift starting with codon Phenylalanine 349, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Phe349LysfsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies indicate that this variant results in loss of enzyme activity (Shi et al., 2017). The c.1045_1051delTTTAAGC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1045_1051delTTTAAGC as pathogenic variant.
OMIM RCV000505812 SCV000600002 pathogenic VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2 2017-09-21 no assertion criteria provided literature only

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