The Ile619Ser missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a non-polar Isoleucine residue is replaced by a polar Serine residue. It alters a conserved position in the C-terminal region of the protein, and multiple in silico algorithms predict it may be damaging to protein structure/function. However, missense mutations have not been reported in this region of the protein in association with epilepsy. Therefore, based on the currently available information, it is unclear whether Ile619Ser is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
ClinVar Genomic variation as it relates to human health
NM_018100.4(EFHC1):c.1856T>G (p.Ile619Ser)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Uncertain significance(2); Likely benign(1)
Uncertain significance(2); Likely benign(1)
3 out of 8 submissions contributed to this classification
Help
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.
4
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_018100.4(EFHC1):c.1856T>G (p.Ile619Ser)
Variation ID: 205416 Accession: VCV000205416.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p12.2 6: 52492274 (GRCh38) [ NCBI UCSC ] 6: 52357072 (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 May 29, 2016 Sep 6, 2025 Nov 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_018100.4:c.1856T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060570.2:p.Ile619Ser missense NM_001172420.2:c.1799T>G NP_001165891.1:p.Ile600Ser missense NR_033327.2:n.3182T>G non-coding transcript variant NC_000006.12:g.52492274T>G NC_000006.11:g.52357072T>G NG_016760.1:g.77079T>G - Protein change
- I619S, I600S
- Other names
-
p.I619S:ATC>AGC
- Canonical SPDI
- NC_000006.12:52492273:T:G
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00260 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00018
1000 Genomes Project 30x 0.00250
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00018
1000 Genomes Project 0.00260
The Genome Aggregation Database (gnomAD), exomes 0.00005
The Genome Aggregation Database (gnomAD) 0.00021
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| EFHC1 | - | - |
GRCh38 GRCh37 |
496 | 513 | |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 2, 2022 | RCV000187374.15 | |
| Likely benign (1) |
criteria provided, single submitter
|
Nov 18, 2024 | RCV003765188.3 | |
|
EFHC1-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Aug 24, 2020 | RCV003927737.2 |
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. |
Expand all rows
Collapse all rows
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 16, 2013)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000240959.11
First in ClinVar: Aug 08, 2015 Last updated: May 29, 2016 |
Comment:
show
The Ile619Ser missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a non-polar Isoleucine residue is replaced by a polar Serine residue. It alters a conserved position in the C-terminal region of the protein, and multiple in silico algorithms predict it may be damaging to protein structure/function. However, missense mutations have not been reported in this region of the protein in association with epilepsy. Therefore, based on the currently available information, it is unclear whether Ile619Ser is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely benign
(Nov 18, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myoclonic epilepsy, juvenile, susceptibility to, 1
Absence seizure
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001008647.7
First in ClinVar: Dec 17, 2019 Last updated: Mar 04, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jun 02, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV004234677.2
First in ClinVar: Feb 04, 2024 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Aug 24, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
EFHC1-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004743362.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
show
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). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
Comment:
Comment:
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).
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Submissions - Functional Data
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0),read abundance - intron inclusion (p=0.0045)
Modifies an exonic cryptic acceptor site at NC_000006.11:g.52357072 from -4.88 to 2.86 bits. Significant p-values: junction spanning - intron inclusion with mutation (4 reads, p=0.0), read abundance - intron inclusion (278 reads, p=0.0045). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006668544.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-C8-A26Z), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Familial cancer of breast
- Transcript, protein change: NM_018100.4:c.1856T>G, I619S
- Molecular phenotype measured: splicing
- Cell line: TCGA-C8-A26Z
- Tissue: Breast Invasive Carcinoma (BRCA)
- Collection method: in vitro
- Species: human
- Number of controls: 616
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0),read abundance - intron inclusion (p=0.0018)
Modifies an exonic cryptic acceptor site at NC_000006.11:g.52357072 from -4.88 to 2.86 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0), read abundance - intron inclusion (45 reads, p=0.0018). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006668545.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-CC-A7IG), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Hepatocellular carcinoma
- Transcript, protein change: NM_018100.4:c.1856T>G, I619S
- Molecular phenotype measured: splicing
- Cell line: TCGA-CC-A7IG
- Tissue: Liver Hepatocellular Carcinoma (LIHC)
- Collection method: in vitro
- Species: human
- Number of controls: 380
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
read abundance - intron inclusion (p=0.041)
Modifies an exonic cryptic acceptor site at NC_000006.11:g.52357072 from -4.88 to 2.86 bits. Significant p-values: read abundance - intron inclusion (26 reads, p=0.041). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006668546.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-CC-5261), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Hepatocellular carcinoma
- Transcript, protein change: NM_018100.4:c.1856T>G, I619S
- Molecular phenotype measured: splicing
- Cell line: TCGA-CC-5261
- Tissue: Liver Hepatocellular Carcinoma (LIHC)
- Collection method: in vitro
- Species: human
- Number of controls: 380
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion (p=0.0031),junction spanning - intron inclusion with mutation (p=0.0),read abundance - intron inclusion (p=0.0055)
Modifies an exonic cryptic acceptor site at NC_000006.11:g.52357072 from -4.88 to 2.86 bits. Significant p-values: junction spanning - intron inclusion (16 reads, p=0.0031), junction spanning - intron inclusion with mutation (12 reads, p=0.0), read abundance - intron inclusion (135 reads, p=0.0055). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006668548.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-BR-A4J7), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Gastric cancer
- Transcript, protein change: NM_018100.4:c.1856T>G, I619S
- Molecular phenotype measured: splicing
- Cell line: TCGA-BR-A4J7
- Tissue: Stomach Adenocarcinoma (STAD)
- Collection method: in vitro
- Species: human
- Number of controls: 660
Text-mined citations for rs142458862 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 22, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.