Submissions for variant NM_018238.4(AGK):c.1141_1142dup (p.Ser382fs)

dbSNP: rs1554405928

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627658	SCV000748658	likely pathogenic	not provided	2018-05-02	criteria provided, single submitter	clinical testing	The c.1141_1142dupGG variant in the AGK gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1141_1142dupGG variant causes a frameshift starting with codon Serine 382, changes this amino acid to a Alanine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Ser382AlafsX17. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1141_1142dupGG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1141_1142dupGG as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696618	SCV000825184	pathogenic	Sengers syndrome; Cataract 38	2022-10-28	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 524160). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the AGK protein in which other variant(s) (p.Tyr390Serfs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with clinical features of Sengers syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser382Alafs*17) in the AGK gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the AGK protein.