VCV000207597.10 - ClinVar

NM_000391.4(TPP1):c.1664C>A (p.Ala555Asp)

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.

(5)

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_000391.4(TPP1):c.1664C>A (p.Ala555Asp)

Variation ID: 207597 Accession: VCV000207597.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 6614574 (GRCh38) [ NCBI UCSC ] 11: 6635805 (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 7, 2015	Mar 30, 2024	Sep 27, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000391.4:c.1664C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000382.3:p.Ala555Asp	missense
NC_000011.10:g.6614574G>T
NC_000011.9:g.6635805G>T
NG_008653.1:g.9888C>A
LRG_830:g.9888C>A
LRG_830t1:c.1664C>A	LRG_830p1:p.Ala555Asp

... more HGVS ... less HGVS

Protein change

A555D

Other names

p.A555D:GCT>GAT

Canonical SPDI

NC_000011.10:6614573:G:T

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), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00005

Links

ClinGen: CA319220 dbSNP: rs200880556 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.
TPP1		-	-	GRCh38 GRCh37	1154	1185

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 provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Sep 27, 2022	RCV000189796.14
Neuronal ceroid lipofuscinosis 2	Uncertain significance (2)	no assertion criteria provided	Nov 10, 2020	RCV001835715.10

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 (Feb 13, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000243444.11 First in ClinVar: Aug 07, 2015 Last updated: Apr 17, 2019	Comment: p.Ala555Asp (GCT>GAT): c.1664 C>A in exon 13 of the TPP1 gene (NM_000391.3)The Ala555Asp missense change has not been published as a mutation, nor has it … (more) p.Ala555Asp (GCT>GAT): c.1664 C>A in exon 13 of the TPP1 gene (NM_000391.3)The Ala555Asp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ala555Asp in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as an uncharged, non-polar Alanine residue is replaced by a negatively charged Aspartic acid residue. However, it alters a position in the protein that is not conserved across species. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ala555Asp is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY,INFANT-EPI panel(s). (less)
Uncertain significance (Sep 27, 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: SCV000830397.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 555 of the TPP1 protein … (more) This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 555 of the TPP1 protein (p.Ala555Asp). This variant is present in population databases (rs200880556, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207597). 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 (Apr 02, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003820946.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Nov 10, 2020)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002094786.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
not provided (-)	no classification provided Method: phenotyping only	Neuronal ceroid lipofuscinosis 2 Affected status: unknown Allele origin: unknown	GenomeConnect - Brain Gene Registry Accession: SCV004804580.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Comment: Variant classified as Uncertain significance and reported on 03-09-2021 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect … (more) Variant classified as Uncertain significance and reported on 03-09-2021 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Abnormal skull morphology (present) , Ptosis (present) , Abnormality of coordination (present) , EEG abnormality (present) , Seizure (present) , Abnormal large intestine morphology (present) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2021-03-09 Testing laboratory interpretation: Uncertain significance

Comment:

p.Ala555Asp (GCT>GAT): c.1664 C>A in exon 13 of the TPP1 gene (NM_000391.3)The Ala555Asp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ala555Asp in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as an uncharged, non-polar Alanine residue is replaced by a negatively charged Aspartic acid residue. However, it alters a position in the protein that is not conserved across species. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ala555Asp is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY,INFANT-EPI panel(s).

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 555 of the TPP1 protein (p.Ala555Asp). This variant is present in population databases (rs200880556, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207597). 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:

Variant classified as Uncertain significance and reported on 03-09-2021 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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 rs200880556 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000391.4(TPP1):c.1664C>A (p.Ala555Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200880556 ...