VCV000372833.25 - ClinVar

NM_001114748.2(TMEM240):c.196G>A (p.Gly66Arg)

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.

(7)

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
Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001114748.2(TMEM240):c.196G>A (p.Gly66Arg)

Variation ID: 372833 Accession: VCV000372833.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.33 1: 1535766 (GRCh38) [ NCBI UCSC ] 1: 1471146 (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	Jan 9, 2017	Oct 26, 2024	Jul 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001114748.2:c.196G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001108220.1:p.Gly66Arg	missense
NC_000001.11:g.1535766C>T
NC_000001.10:g.1471146C>T
NG_041807.1:g.9595G>A
NG_053035.1:g.28624C>T

... more HGVS ... less HGVS

Protein change

G66R

Other names

Canonical SPDI

NC_000001.11:1535765:C: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.

Links

ClinGen: CA16042311 dbSNP: rs1057518011 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.
TMEM240		-	-	GRCh38 GRCh37	122	275

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	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 1, 2023	RCV000413958.18
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2020	RCV001267568.4
Spinocerebellar ataxia type 21	Pathogenic (3)	criteria provided, single submitter	Jan 4, 2021	RCV001542542.4

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 pathogenic (Jan 27, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491361.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Comment: The G66R variant in the TMEM240 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more) The G66R variant in the TMEM240 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G66R variant was not observed in approximately 2300 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 G66R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret G66R as a likely pathogenic variant. (less)
Pathogenic (Jan 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Spinocerebellar ataxia type 21 Affected status: yes Allele origin: de novo	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris Accession: SCV001519239.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Pathogenic (Aug 04, 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: SCV002294987.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 30522958 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 372833). This missense change has been observed in individual(s) with clinical features of TMEM240-related spinocerebellar ataxia (PMID: 30522958; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 66 of the TMEM240 protein (p.Gly66Arg). (less)
Uncertain significance (Mar 31, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001445750.4 First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 30522958 Comment: The alteration results in an amino acid change:_x000D_ _x000D_ The c.196G>A (p.G66R) alteration is located in coding exon 3 of the TMEM240 gene. This alteration … (more) The alteration results in an amino acid change:_x000D_ _x000D_ The c.196G>A (p.G66R) alteration is located in coding exon 3 of the TMEM240 gene. This alteration results from a G to A substitution at nucleotide position 196, causing the glycine (G) at amino acid position 66 to be replaced by an arginine (R). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the TMEM240 c.196G>A alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was described in 2 siblings with childhood-onset cerebellar ataxia, posural tremor, hypmimia, motor delay, intellectual disability, and behavioral abnormalities (Traschütz, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.G66 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.G66R alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Pathogenic (Jul 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: SCV004032539.11 First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024	Comment: TMEM240: PP1:Strong, PM2, PM6, PS4:Moderate, PP3 Number of individuals with the variant: 1
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Spinocerebellar ataxia type 21 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001759979.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Spinocerebellar ataxia type 21 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091507.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team

Comment:

The G66R variant in the TMEM240 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G66R variant was not observed in approximately 2300 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 G66R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret G66R as a likely pathogenic variant.

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 372833). This missense change has been observed in individual(s) with clinical features of TMEM240-related spinocerebellar ataxia (PMID: 30522958; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 66 of the TMEM240 protein (p.Gly66Arg).

Comment:

The alteration results in an amino acid change:_x000D_ _x000D_ The c.196G>A (p.G66R) alteration is located in coding exon 3 of the TMEM240 gene. This alteration results from a G to A substitution at nucleotide position 196, causing the glycine (G) at amino acid position 66 to be replaced by an arginine (R). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the TMEM240 c.196G>A alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was described in 2 siblings with childhood-onset cerebellar ataxia, posural tremor, hypmimia, motor delay, intellectual disability, and behavioral abnormalities (Traschütz, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.G66 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.G66R alteration is inconclusive. 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
The movement disorder spectrum of SCA21 (ATX-TMEM240): 3 novel families and systematic review of the literature.	Traschütz A	Parkinsonism & related disorders	2019	PMID: 30522958

Text-mined citations for rs1057518011 ...

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_001114748.2(TMEM240):c.196G>A (p.Gly66Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057518011 ...