NM_000298.6(PKLR):c.1493G>A (p.Arg498His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 10, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001782644.9

Allele description [Variation Report for NM_000298.6(PKLR):c.1493G>A (p.Arg498His)]

NM_000298.6(PKLR):c.1493G>A (p.Arg498His)

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.1493G>A (p.Arg498His)

HGVS:

NC_000001.11:g.155291881C>T
NG_011677.1:g.14554G>A
NM_000298.6:c.1493G>AMANE SELECT
NM_181871.4:c.1400G>A
NP_000289.1:p.Arg498His
NP_870986.1:p.Arg467His
LRG_1136t1:c.1493G>A
LRG_1136:g.14554G>A
LRG_1136p1:p.Arg498His
NC_000001.10:g.155261672C>T

Protein change:

R467H

Links:

dbSNP: rs758327704

NCBI 1000 Genomes Browser:

rs758327704

Molecular consequence:

NM_000298.6:c.1493G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181871.4:c.1400G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002024661	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002174209	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 12, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9482576, 29396846, 17574881, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002024661

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 10, 2022)

germline

clinical testing

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

SCV002174209

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 12, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Novel mutations and structural implications in R-type pyruvate kinase-deficient patients from Southern Italy.

Pastore L, Della Morte R, Frisso G, Alfinito F, Vitale D, Calise RM, Ferraro F, Zagari A, Rotoli B, Salvatore F.

Hum Mutat. 1998;11(2):127-34.

PubMed [citation]

PMID:: 9482576

See all PubMed Citations (5)

Details of each submission

From Revvity Omics, Revvity, SCV002024661.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002174209.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg498 amino acid residue in PKLR. Other variant(s) that disrupt this residue have been observed in individuals with PKLR-related conditions (PMID: 9482576, 17574881, 29396846), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with pyruvate kinase deficiency (PMID: 17574881). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with histidine at codon 498 of the PKLR protein (p.Arg498His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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