VCV002514464.5 - ClinVar

NM_000041.4(APOE):c.192G>C (p.Gln64His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000041.4(APOE):c.192G>C (p.Gln64His)

Variation ID: 2514464 Accession: VCV002514464.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.32 19: 44907908 (GRCh38) [ NCBI UCSC ] 19: 45411165 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 8, 2023	Nov 24, 2024	Feb 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000041.4:c.192G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000032.1:p.Gln64His	missense
NM_000041.3:c.192G>C
NM_001302688.2:c.270G>C	NP_001289617.1:p.Gln90His	missense
NM_001302689.2:c.192G>C	NP_001289618.1:p.Gln64His	missense
NM_001302690.2:c.192G>C	NP_001289619.1:p.Gln64His	missense
NM_001302691.2:c.192G>C	NP_001289620.1:p.Gln64His	missense
NC_000019.10:g.44907908G>C
NC_000019.9:g.45411165G>C
NG_007084.2:g.7127G>C

... more HGVS ... less HGVS

Protein change

Q90H, Q64H

Other names

p.Gln64His

Canonical SPDI

NC_000019.10:44907907:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
APOE		-	-	GRCh38 GRCh37	-	-

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
APOE-related disorder	Uncertain significance (1)	no assertion criteria provided	Feb 21, 2024	RCV003919041.2
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	May 8, 2023	RCV004289067.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Feb 23, 2024	RCV004790515.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (May 08, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003938437.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 30420299‚ 33761857 Comment: The c.192G>C (p.Q64H) alteration is located in coding exon 2 of the APOE gene. This alteration results from a G to C substitution at nucleotide … (more) The c.192G>C (p.Q64H) alteration is located in coding exon 2 of the APOE gene. This alteration results from a G to C substitution at nucleotide position 192, causing the glutamine (Q) at amino acid position 64 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of 0.014% (39/282096) total alleles studied. The highest observed frequency was 0.12% (24/19934) of East Asian alleles. This variant has been reported as a variant of unknown significance in one patient with primary severe high triglyercides (Jin, 2018). This has also been detected in one Southern Chinese patient with late onset Alzheimer's Disease as well as in one control subject (Yee, 2021). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005408854.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 15256764‚ 30420299‚ 33761857‚ 34058468 Comment: BS1 Number of individuals with the variant: 1
Uncertain significance (Feb 21, 2024)	no assertion criteria provided Method: clinical testing	APOE-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004735187.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The APOE c.192G>C variant is predicted to result in the amino acid substitution p.Gln64His. This variant was reported in individuals with hyperlipidemia (described as p.Gln46His, … (more) The APOE c.192G>C variant is predicted to result in the amino acid substitution p.Gln64His. This variant was reported in individuals with hyperlipidemia (described as p.Gln46His, Maruyama et al. 2004. PubMed ID: 15256764; Table S2, Jin et al. 2018. PubMed ID: 30420299). This variant is reported in 0.12% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

The c.192G>C (p.Q64H) alteration is located in coding exon 2 of the APOE gene. This alteration results from a G to C substitution at nucleotide position 192, causing the glutamine (Q) at amino acid position 64 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of 0.014% (39/282096) total alleles studied. The highest observed frequency was 0.12% (24/19934) of East Asian alleles. This variant has been reported as a variant of unknown significance in one patient with primary severe high triglyercides (Jin, 2018). This has also been detected in one Southern Chinese patient with late onset Alzheimer's Disease as well as in one control subject (Yee, 2021). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

The APOE c.192G>C variant is predicted to result in the amino acid substitution p.Gln64His. This variant was reported in individuals with hyperlipidemia (described as p.Gln46His, Maruyama et al. 2004. PubMed ID: 15256764; Table S2, Jin et al. 2018. PubMed ID: 30420299). This variant is reported in 0.12% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
APOE gene variants in primary dyslipidemia.	Khalil YA	Atherosclerosis	2021	PMID: 34058468
Apolipoprotein E Gene Revisited: Contribution of Rare Variants to Alzheimer's Disease Susceptibility in Southern Chinese.	Yee A	Current Alzheimer research	2021	PMID: 33761857
Intensive genetic analysis for Chinese patients with very high triglyceride levels: Relations of mutations to triglyceride levels and acute pancreatitis.	Jin JL	EBioMedicine	2018	PMID: 30420299
Mutations in Japanese subjects with primary hyperlipidemia--results from the Research Committee of the Ministry of Health and Welfare of Japan since 1996--.	Maruyama T	Journal of atherosclerosis and thrombosis	2004	PMID: 15256764

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000041.4(APOE):c.192G>C (p.Gln64His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...