NM_000298.6(PKLR):c.1516G>A (p.Val506Ile) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(3) (Last evaluated: Jan 12, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000224042.7

Allele description [Variation Report for NM_000298.6(PKLR):c.1516G>A (p.Val506Ile)]

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

Gene:
PKLR:pyruvate kinase L/R [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_000298.6(PKLR):c.1516G>A (p.Val506Ile)
HGVS:
  • NC_000001.11:g.155291858C>T
  • NG_011677.1:g.14577G>A
  • NM_000298.6:c.1516G>AMANE SELECT
  • NM_181871.4:c.1423G>A
  • NP_000289.1:p.Val506Ile
  • NP_870986.1:p.Val475Ile
  • LRG_1136t1:c.1516G>A
  • LRG_1136:g.14577G>A
  • LRG_1136p1:p.Val506Ile
  • NC_000001.10:g.155261649C>T
  • NM_000298.5:c.1516G>A
  • P30613:p.Val506Ile
Protein change:
V475I
Links:
UniProtKB: P30613#VAR_018848; dbSNP: rs8177988
NCBI 1000 Genomes Browser:
rs8177988
Molecular consequence:
  • NM_000298.6:c.1516G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181871.4:c.1423G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000280976Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinicscriteria provided, single submitter
Uncertain Significance
(Feb 6, 2015)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000617805GeneDxcriteria provided, single submitter
Uncertain significance
(Oct 3, 2017)
germlineclinical testing

Citation Link,

SCV001117732Invitaecriteria provided, single submitter
Likely benign
(Dec 31, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001549750Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

SCV001713041Mayo Clinic Laboratories, Mayo Cliniccriteria provided, single submitter
Uncertain significance
(Jan 12, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown3not providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics, SCV000280976.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Converted during submission to Uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot provided0.006166not providednot provided

From GeneDx, SCV000617805.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001117732.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001549750.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001713041.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided3not providednot providednot provided

Last Updated: Jun 14, 2021

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