NM_002693.3(POLG):c.1837C>T (p.His613Tyr) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Feb 19, 2024
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:: RCV000173762.32

Allele description [Variation Report for NM_002693.3(POLG):c.1837C>T (p.His613Tyr)]

NM_002693.3(POLG):c.1837C>T (p.His613Tyr)

Gene:

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_002693.3(POLG):c.1837C>T (p.His613Tyr)

Other names:

p.H613Y:CAC>TAC

HGVS:

NC_000015.10:g.89325562G>A
NG_008218.2:g.14234C>T
NM_001126131.2:c.1837C>T
NM_002693.3:c.1837C>TMANE SELECT
NP_001119603.1:p.His613Tyr
NP_002684.1:p.His613Tyr
NP_002684.1:p.His613Tyr
LRG_765t1:c.1837C>T
LRG_765:g.14234C>T
LRG_765p1:p.His613Tyr
NC_000015.9:g.89868793G>A
NM_002693.2:c.1837C>T

Protein change:

H613Y

Links:

dbSNP: rs147407423

NCBI 1000 Genomes Browser:

rs147407423

Molecular consequence:

NM_001126131.2:c.1837C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.1837C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000224911	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Benign (Apr 2, 2015)	germline	clinical testing	Citation Link,
SCV000596502	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 14, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000604902	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jan 17, 2017)	germline	clinical testing	Citation Link,
SCV004813937	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 19, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	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 POLG mutations and variable clinical phenotypes in 13 Italian patients.

Da Pozzo P, Cardaioli E, Rubegni A, Gallus GN, Malandrini A, Rufa A, Battisti C, Carluccio MA, Rocchi R, Giannini F, Bianchi A, Mancuso M, Siciliano G, Dotti MT, Federico A.

Neurol Sci. 2017 Apr;38(4):563-570. doi: 10.1007/s10072-016-2734-3. Epub 2017 Jan 27.

PubMed [citation]

PMID:: 28130605

Details of each submission

From Eurofins Ntd Llc (ga), SCV000224911.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	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		2	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000596502.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604902.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813937.1

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

Description

Variant summary: POLG c.1837C>T (p.His613Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 1613624 control chromosomes, predominantly at a frequency of 0.0046 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. c.1837C>T has been reported in the literature in an individual with features POLG-Related Spectrum Disorders (Pozzo_2017). This report does not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28130605). ClinVar contains an entry for this variant (Variation ID: 193643). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Oct 20, 2024

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