Submissions for variant NM_000298.6(PKLR):c.1516G>A (p.Val506Ile)

gnomAD frequency: 0.00414  dbSNP: rs8177988

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224042	SCV000280976	uncertain significance	not provided	2015-02-06	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000224042	SCV000617805	uncertain significance	not provided	2017-10-03	criteria provided, single submitter	clinical testing	The V506I variant in the PKLR gene, also called PK Mallorca, has been reported previously in the heterozygous state with a second PKLR variant in a patient with PK deficiency (Pissard et al., 2006). The V506I variant was also identified in the heterozygous state in a child with concomitant hereditary spherocytosis and chronic hemolytic anemia who harbored V506I in trans with variants in hereditary spherocytosis genes; this individual's mother with V506I in the heterozygous state was asymptomatic (Zarza et al., 2000). The V506I variant is observed in 217/30782 (0.7%) alleles from individuals of South African background, including five homozygous individuals, in the ExAC dataset (Lek et al., 2016). The V506I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V506I as a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224042	SCV000885965	uncertain significance	not provided	2023-04-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764981	SCV000896160	uncertain significance	Pyruvate kinase hyperactivity; Pyruvate kinase deficiency of red cells	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000224042	SCV001117732	likely benign	not provided	2023-12-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095923	SCV001252102	likely benign	Pyruvate kinase deficiency of red cells	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224042	SCV001713041	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BP4_strong
CeGaT Center for Human Genetics Tuebingen	RCV000224042	SCV004124920	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PKLR: BS2
PreventionGenetics, part of Exact Sciences	RCV003929928	SCV004739373	likely benign	PKLR-related condition	2023-02-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000224042	SCV001549750	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PKLR p.Val475Ile variant was identified in 1 of 112 proband chromosomes (frequency: 0.0089) from individuals or families with pyruvate-kinase deficiency (Pissard_2006_PMID:16704447). The variant was also identified in the heterozygous state in a patient with partial red blood cell pyruvate-kinase deficiency concomitant hereditary spherocytosis and chronic hemolytic anemia; the patient's unaffected mother also carried the V475I variant (Zarza_2000_PMID:10702808). The variant was identified in dbSNP (ID: rs8177988), ClinVar (classified as a VUS by ARUP Laboratories, GeneDx, Fulgent Genetics and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) and LOVD 3.0 (classified as a VUS and pathogenic). The variant was identified in control databases in 1201 of 282864 chromosomes (5 homozygous) at a frequency of 0.004246 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 221 of 30616 chromosomes (freq: 0.007218), European (non-Finnish) in 769 of 129180 chromosomes (freq: 0.005953), Other in 37 of 7224 chromosomes (freq: 0.005122), Latino in 93 of 35436 chromosomes (freq: 0.002624), Ashkenazi Jewish in 21 of 10368 chromosomes (freq: 0.002025), European (Finnish) in 31 of 25120 chromosomes (freq: 0.001234) and African in 29 of 24966 chromosomes (freq: 0.001162); it was not observed in the East Asian population. The p.Val475 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.