Submissions for variant NM_000298.6(PKLR):c.1178A>G (p.Asn393Ser)

gnomAD frequency: 0.00001  dbSNP: rs776594413

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001546580	SCV001766118	likely pathogenic	not provided	2021-04-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33054133, 31747117, 16540430, 19085939, 16704447, 27432187, 15982340, 7706479, 17382129)
Mendelics	RCV002246424	SCV002517367	likely pathogenic	Pyruvate kinase hyperactivity	2022-05-04	criteria provided, single submitter	clinical testing
3billion	RCV002250766	SCV002521021	likely pathogenic	Pyruvate kinase deficiency of red cells	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PKLR related disorder (ClinVar ID: VCV001187215 / PMID: 7706479). Different missense changes at the same codon (p.Asn393Asp, p.Asn393Lys) have been reported to be associated with PKLR related disorder (PMID: 16704447, 7706479). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001546580	SCV004292893	pathogenic	not provided	2023-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 393 of the PKLR protein (p.Asn393Ser). This variant is present in population databases (rs776594413, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of pyruvate kinase deficiency (PMID: 7706479, 16704447, 17360088, 27432187, 31747117). ClinVar contains an entry for this variant (Variation ID: 1187215). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKLR protein function. This variant disrupts the p.Asn393 amino acid residue in PKLR. Other variant(s) that disrupt this residue have been observed in individuals with PKLR-related conditions (PMID: 7706479, 16704447), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV002250766	SCV005400882	likely pathogenic	Pyruvate kinase deficiency of red cells	2023-06-22	criteria provided, single submitter	clinical testing	The missense variant c.1178A>G(p.Asn393Ser) in PKLR gene has been observed in compound heterozygous state in multiple individual(s) with pyruvate kinase deficiency (Rab et. al., 2021; Van Wijk et. al., 2009). The observed variant has allele frequency of 0.0008% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic (multiple submitters). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Asn393Ser in PKLR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Different missense changes at the same codon (p.Asn393Asp, p.Asn393Lys) have been reported to be associated with PKLR related disorder (Baronciani et. al, 1995). The amino acid Asn at position 393 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. However, functional studies will be required to cofirm the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.