VCV000364564.23 - ClinVar

NM_003640.5(ELP1):c.2803A>T (p.Thr935Ser)

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.

(9)

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_003640.5(ELP1):c.2803A>T (p.Thr935Ser)

Variation ID: 364564 Accession: VCV000364564.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q31.3 9: 108894000 (GRCh38) [ NCBI UCSC ] 9: 111656280 (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	Dec 6, 2016	May 1, 2024	Dec 19, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_003640.5:c.2803A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003631.2:p.Thr935Ser	missense
NM_001318360.2:c.2461A>T	NP_001305289.1:p.Thr821Ser	missense
NM_001330749.2:c.1756A>T	NP_001317678.1:p.Thr586Ser	missense
NC_000009.12:g.108894000T>A
NC_000009.11:g.111656280T>A
NG_008788.1:g.45329A>T
LRG_251:g.45329A>T
LRG_251t1:c.2803A>T

... more HGVS ... less HGVS

Protein change

T935S, T821S, T586S

Other names

Canonical SPDI

NC_000009.12:108893999:T:A

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.

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA5174532 dbSNP: rs145484092 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.
ELP1		-	-	GRCh38 GRCh37	2069	2113

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.
Familial dysautonomia	Uncertain significance (2)	criteria provided, single submitter	Jan 13, 2018	RCV000351107.8
not provided	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Aug 10, 2022	RCV000757403.16
Medulloblastoma	Uncertain significance (1)	criteria provided, single submitter	Dec 19, 2022	RCV002291624.2
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 22, 2022	RCV004022094.1

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 (Jun 15, 2017)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885609.1 First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019	Comment: The p.Thr935Ser variant (rs14548409) has been reported as a variant of uncertain significance that was detected twice in a large cohort of patients with idiopathic … (more) The p.Thr935Ser variant (rs14548409) has been reported as a variant of uncertain significance that was detected twice in a large cohort of patients with idiopathic peripheral neuropathy (Antoniardi 2015). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 364564). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in European populations of 0.008% (identified on 10 out of 126,420 chromosomes). The threonine at codon 935 is moderately conserved (Alamut software v2.9.0), however several species including cape golden mole, lizard, Atlantic cod and lamprey have a serine at this position, suggesting this change may be evolutionary tolerated. Computational analyses return mixed predictions regarding the effect on IKBKAP protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial dysautonomia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000476558.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Aug 10, 2022)	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: SCV000816487.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 935 of the ELP1 protein (p.Thr935Ser). … (more) This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 935 of the ELP1 protein (p.Thr935Ser). This variant is present in population databases (rs145484092, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 364564). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 (Mar 21, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001994756.2 First in ClinVar: Nov 05, 2021 Last updated: Mar 04, 2023	Comment: Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more) Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Dec 19, 2022)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Medulloblastoma Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV002584771.2 First in ClinVar: Oct 22, 2022 Last updated: Mar 26, 2023	Comment: The ELP1 c.2803A>T (p.Thr935Ser) missense change has a maximum subpopulation frequency of 0.0078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more) The ELP1 c.2803A>T (p.Thr935Ser) missense change has a maximum subpopulation frequency of 0.0078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with Charcot-Marie-Tooth disease and in an individual with hereditary motor neuropathy (PMID: 26392352). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
Uncertain significance (Jan 22, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002755068.2 First in ClinVar: Dec 03, 2022 Last updated: May 01, 2024	Comment: The c.2803A>T (p.T935S) alteration is located in exon 26 (coding exon 25) of the IKBKAP gene. This alteration results from a A to T substitution … (more) The c.2803A>T (p.T935S) alteration is located in exon 26 (coding exon 25) of the IKBKAP gene. This alteration results from a A to T substitution at nucleotide position 2803, causing the threonine (T) at amino acid position 935 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Familial dysautonomia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457896.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917276.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927242.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021

Comment:

The p.Thr935Ser variant (rs14548409) has been reported as a variant of uncertain significance that was detected twice in a large cohort of patients with idiopathic peripheral neuropathy (Antoniardi 2015). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 364564). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in European populations of 0.008% (identified on 10 out of 126,420 chromosomes). The threonine at codon 935 is moderately conserved (Alamut software v2.9.0), however several species including cape golden mole, lizard, Atlantic cod and lamprey have a serine at this position, suggesting this change may be evolutionary tolerated. Computational analyses return mixed predictions regarding the effect on IKBKAP protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 935 of the ELP1 protein (p.Thr935Ser). This variant is present in population databases (rs145484092, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 364564). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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:

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Comment:

The ELP1 c.2803A>T (p.Thr935Ser) missense change has a maximum subpopulation frequency of 0.0078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with Charcot-Marie-Tooth disease and in an individual with hereditary motor neuropathy (PMID: 26392352). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

Comment:

The c.2803A>T (p.T935S) alteration is located in exon 26 (coding exon 25) of the IKBKAP gene. This alteration results from a A to T substitution at nucleotide position 2803, causing the threonine (T) at amino acid position 935 to be replaced by a serine (S). 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

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.

Text-mined citations for rs145484092 ...

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 27, 2024

ClinVar Genomic variation as it relates to human health

NM_003640.5(ELP1):c.2803A>T (p.Thr935Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145484092 ...