VCV000252629.24 - ClinVar

NM_004447.6(EPS8):c.1330T>C (p.Phe444Leu)

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004447.6(EPS8):c.1330T>C (p.Phe444Leu)

Variation ID: 252629 Accession: VCV000252629.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p12.3 12: 15650927 (GRCh38) [ NCBI UCSC ] 12: 15803861 (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	Aug 1, 2016	Oct 20, 2024	Dec 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004447.6:c.1330T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004438.3:p.Phe444Leu	missense
NC_000012.12:g.15650927A>G
NC_000012.11:g.15803861A>G
NG_041808.1:g.143650T>C

Protein change

F444L

Other names

Canonical SPDI

NC_000012.12:15650926:A:G

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.

0.00080 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

Exome Aggregation Consortium (ExAC) 0.00040

The Genome Aggregation Database (gnomAD), exomes 0.00055

1000 Genomes Project 30x 0.00062

1000 Genomes Project 0.00080

The Genome Aggregation Database (gnomAD) 0.00081

Trans-Omics for Precision Medicine (TOPMed) 0.00087

Links

ClinGen: CA6467597 dbSNP: rs139258361 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.
EPS8		-	-	GRCh38 GRCh37	292	334

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.
not specified	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Oct 29, 2018	RCV000239190.7
Deafness	not provided (1)	no classification provided	-	RCV000509335.1
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Dec 27, 2023	RCV000733660.21
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 11, 2021	RCV002518520.2

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.	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.
Likely benign (Oct 29, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966432.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Comment: The p.Phe444Leu variant in EPS8 is classified as likely benign because it has be en identified in 0.1% (34/34404) of Latino chromosomes by gnomAD (http://gnomad. … (more) The p.Phe444Leu variant in EPS8 is classified as likely benign because it has be en identified in 0.1% (34/34404) of Latino chromosomes by gnomAD (http://gnomad. broadinstitute.org), and computational prediction tools and conservation analysi s suggest that this variant may not impact the protein. ACMG/AMP Criteria applie d: BS1_Supporting, BP4. (less) Number of individuals with the variant: 1
Likely benign (Mar 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001819565.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Uncertain significance (Nov 16, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000297160.3 First in ClinVar: Aug 01, 2016 Last updated: Dec 24, 2022
Uncertain significance (Dec 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002263243.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 444 of the EPS8 protein (p.Phe444Leu). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 444 of the EPS8 protein (p.Phe444Leu). This variant is present in population databases (rs139258361, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with EPS8-related conditions. ClinVar contains an entry for this variant (Variation ID: 252629). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EPS8 protein function with a negative predictive value of 80%. 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. (less)
Uncertain significance (Jun 11, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003658724.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.1330T>C (p.F444L) alteration is located in exon 14 (coding exon 13) of the EPS8 gene. This alteration results from a T to C substitution … (more) The c.1330T>C (p.F444L) alteration is located in exon 14 (coding exon 13) of the EPS8 gene. This alteration results from a T to C substitution at nucleotide position 1330, causing the phenylalanine (F) at amino acid position 444 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Likely benign (Nov 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004184223.9 First in ClinVar: Dec 24, 2023 Last updated: Oct 20, 2024	Comment: EPS8: BS1:Supporting Number of individuals with the variant: 1
Uncertain significance (Jun 22, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000861750.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EPS8 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
not provided (-)	no classification provided Method: phenotyping only	Deafness Affected status: unknown Allele origin: paternal	GenomeConnect, ClinGen Accession: SCV000606923.1 First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Abnormal delivery (present) , Decreased fetal movement (present) , Abnormality of the amniotic fluid (present) , Growth hormone deficiency (present) , Failure to thrive (present) … (more) Abnormal delivery (present) , Decreased fetal movement (present) , Abnormality of the amniotic fluid (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hyperthyroidism (present) , Hypogonadism (present) , Oral-pharyngeal dysphagia (present) , Abnormality of the skull (present) , Abnormality of the nose (present) , Abnormality of the oral cavity (present) , Abnormality of the hair (present) , Abnormal facial shape (present) , Abnormality of the chin (present) , Hypermetropia (present) , Abnormality of vision (present) , Hearing impairment (present) , Aplasia/Hypoplasia of the ear (present) , Seizures (present) , Abnormality of movement (present) , Generalized hypotonia (present) , Encephalopathy (present) , EEG abnormality (present) , Cognitive impairment (present) , Morphological abnormality of the central nervous system (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the upper respiratory tract (present) , Abnormal pattern of respiration (present) , Respiratory insufficiency (present) , Abnormality of the diaphragm (present) , Abnormality of the stomach (present) , Feeding difficulties (present) , Abnormality of the male genitalia (present) , Abnormal renal physiology (present) , Abnormality of the bladder (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Testing laboratory: Division of Genomic Diagnostics,The Children's Hospital of Philadelphia Date variant was reported to submitter: 2015-11-16 Testing laboratory interpretation: Uncertain significance

Comment:

The p.Phe444Leu variant in EPS8 is classified as likely benign because it has be en identified in 0.1% (34/34404) of Latino chromosomes by gnomAD (http://gnomad. broadinstitute.org), and computational prediction tools and conservation analysi s suggest that this variant may not impact the protein. ACMG/AMP Criteria applie d: BS1_Supporting, BP4.

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 444 of the EPS8 protein (p.Phe444Leu). This variant is present in population databases (rs139258361, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with EPS8-related conditions. ClinVar contains an entry for this variant (Variation ID: 252629). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EPS8 protein function with a negative predictive value of 80%. 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.

Comment:

The c.1330T>C (p.F444L) alteration is located in exon 14 (coding exon 13) of the EPS8 gene. This alteration results from a T to C substitution at nucleotide position 1330, causing the phenylalanine (F) at amino acid position 444 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EPS8	-	-	-	-

Text-mined citations for rs139258361 ...

These 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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_004447.6(EPS8):c.1330T>C (p.Phe444Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139258361 ...