VCV000161192.70 - ClinVar

NM_001114748.2(TMEM240):c.509C>T (p.Pro170Leu)

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.

(12)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001114748.2(TMEM240):c.509C>T (p.Pro170Leu)

Variation ID: 161192 Accession: VCV000161192.70

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.33 1: 1535372 (GRCh38) [ NCBI UCSC ] 1: 1470752 (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 7, 2014	Oct 20, 2024	Jan 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001114748.2:c.509C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001108220.1:p.Pro170Leu	missense
NC_000001.11:g.1535372G>A
NC_000001.10:g.1470752G>A
NG_041807.1:g.9989C>T
NG_053035.1:g.28230G>A
	Q5SV17:p.Pro170Leu

... more HGVS ... less HGVS

Protein change

P170L

Other names

Canonical SPDI

NC_000001.11:1535371:G: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.

Links

ClinGen: CA272844 UniProtKB: Q5SV17#VAR_071909 OMIM: 616101.0001 dbSNP: rs606231451 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 (4)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV000322616.37
Spinocerebellar ataxia type 21	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jan 12, 2024	RCV000148344.27

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 (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446440.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cerebellar ataxia (present) , Myoclonus (present) Sex: female
Pathogenic (Oct 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: SCV001250212.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: TMEM240: PS2:Very Strong, PM2 Number of individuals with the variant: 5
Pathogenic (Jan 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia type 21 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV005043987.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Comment: PS2_VS, PS4, PM2
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia type 21 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769210.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 25070513‚ 33851480 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function is likely (PMID: 25070513). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as a recurrent variant in multiple unrelated individuals with spinocerebellar ataxia (PMIDs: 25070513, 33851480). It has also been reported as likely pathogenic/pathogenic in ClinVar. (SP) 0901 - This variant has strong evidence for segregation with disease. It has been reported to segregate with disease in many affected individuals across three generations in two unrelated families (PMID: 25070513). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely pathogenic (Mar 28, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450010.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 1
Pathogenic (Jul 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia type 21 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556705.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Publications: PubMed (1) PubMed: 25070513 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: Variant is predicted to result in a missense amino … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: Variant is predicted to result in a missense amino acid change from proline to leucine. The mechanism of disease for this gene is not clearly established. However, gain of function is likely (PMID: 25070513). This gene is associated with autosomal dominant disease. Variant is absent from gnomAD (both v2 and v3). (SP) An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). Missense variant with conflicting in silico predictions and high conservation. This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as a recurrent variant in multiple unrelated individuals with spinocerebellar ataxia (PMIDs: 25070513, 33851480). It has also been reported as likely pathogenic/pathogenic in ClinVar. (SP) This variant has strong evidence for segregation with disease. It has been reported to segregate with disease in many affected individuals across three generations in two unrelated families (PMID: 25070513). (SP) (less)
Pathogenic (Apr 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Spinocerebellar ataxia type 21 Affected status: yes Allele origin: germline	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) Accession: SCV003920741.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023
Likely pathogenic (Jun 08, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia 21 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000597502.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015
Pathogenic (Jan 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Spinocerebellar ataxia type 21 Affected status: yes Allele origin: unknown	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris Accession: SCV001519238.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Pathogenic (May 31, 2021)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Spinocerebellar ataxia type 21 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764933.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Cerebellar ataxia (present) , Cerebellar atrophy (present) , Dystonic disorder (present)
Pathogenic (Mar 09, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000330042.9 First in ClinVar: Dec 06, 2016 Last updated: Mar 18, 2023	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30522958, 30184469, 32816195, 25070513, 29687291, 26813285, 29915382, 31692161, 33669240, 33726816, 35872528, 34445196) (less)
Pathogenic (Oct 01, 2014)	no assertion criteria provided Method: literature only	SPINOCEREBELLAR ATAXIA 21 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000195808.2 First in ClinVar: Dec 07, 2014 Last updated: Aug 18, 2024	Publications: PubMed (2) PubMed: 11160961‚ 25070513 Comment on evidence: In affected members of a large French family with spinocerebellar ataxia-21 (SCA21; 607454), originally reported by Devos et al. (2001), Delplanque et al. (2014) identified … (more) In affected members of a large French family with spinocerebellar ataxia-21 (SCA21; 607454), originally reported by Devos et al. (2001), Delplanque et al. (2014) identified a heterozygous c.509C-T transition in exon 4 of the TMEM240 gene, resulting in a pro170-to-leu (P170L) substitution at a highly conserved residue at the C terminus. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 934 French controls. The same mutation was subsequently identified in affected members of 2 of 368 French families with a similar disorder, but haplotype analysis did not suggest a founder effect among these families. Functional studies of the variant were not performed. (less)
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Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function is likely (PMID: 25070513). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as a recurrent variant in multiple unrelated individuals with spinocerebellar ataxia (PMIDs: 25070513, 33851480). It has also been reported as likely pathogenic/pathogenic in ClinVar. (SP) 0901 - This variant has strong evidence for segregation with disease. It has been reported to segregate with disease in many affected individuals across three generations in two unrelated families (PMID: 25070513). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: Variant is predicted to result in a missense amino acid change from proline to leucine. The mechanism of disease for this gene is not clearly established. However, gain of function is likely (PMID: 25070513). This gene is associated with autosomal dominant disease. Variant is absent from gnomAD (both v2 and v3). (SP) An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). Missense variant with conflicting in silico predictions and high conservation. This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as a recurrent variant in multiple unrelated individuals with spinocerebellar ataxia (PMIDs: 25070513, 33851480). It has also been reported as likely pathogenic/pathogenic in ClinVar. (SP) This variant has strong evidence for segregation with disease. It has been reported to segregate with disease in many affected individuals across three generations in two unrelated families (PMID: 25070513). (SP)

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30522958, 30184469, 32816195, 25070513, 29687291, 26813285, 29915382, 31692161, 33669240, 33726816, 35872528, 34445196)

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
A next generation sequencing-based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21.	Riso V	European journal of neurology	2021	PMID: 33851480
TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment.	Delplanque J	Brain : a journal of neurology	2014	PMID: 25070513
Clinical features and genetic analysis of a new form of spinocerebellar ataxia.	Devos D	Neurology	2001	PMID: 11160961

Text-mined citations for rs606231451 ...

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_001114748.2(TMEM240):c.509C>T (p.Pro170Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs606231451 ...