NM_001114748.2(TMEM240):c.509C>T (p.Pro170Leu) AND Spinocerebellar ataxia type 21

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jan 12, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000148344.25

Allele description

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

Gene:

TMEM240:transmembrane protein 240 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.33

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.1535372G>A
NG_041807.1:g.9989C>T
NG_053035.1:g.28230G>A
NM_001114748.2:c.509C>TMANE SELECT
NP_001108220.1:p.Pro170Leu
NC_000001.10:g.1470752G>A
NM_001114748.1:c.509C>T
Q5SV17:p.Pro170Leu

Protein change:

P170L; PRO170LEU

Links:

UniProtKB: Q5SV17#VAR_071909; OMIM: 616101.0001; dbSNP: rs606231451

NCBI 1000 Genomes Browser:

rs606231451

Molecular consequence:

NM_001114748.2:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Spinocerebellar ataxia type 21 (SCA21)
Identifiers:: MONDO: MONDO:0011833; MedGen: C1843891; Orphanet: 98773; OMIM: 607454

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000195808	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11160961, 25070513
SCV000597502	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 8, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001519238	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2021)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV002556705	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25070513, 25741868
SCV002764933	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (May 31, 2021)	germline	clinical testing	Citation Link,
SCV002769210	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 31, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25070513, 33851480, 25741868
SCV003920741	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 27, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV005043987	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Clinical features and genetic analysis of a new form of spinocerebellar ataxia.

Devos D, Schraen-Maschke S, Vuillaume I, Dujardin K, Nazé P, Willoteaux C, Destée A, Sablonnière B.

Neurology. 2001 Jan 23;56(2):234-8.

PubMed [citation]

PMID:: 11160961

TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment.

Delplanque J, Devos D, Huin V, Genet A, Sand O, Moreau C, Goizet C, Charles P, Anheim M, Monin ML, Buée L, Destée A, Grolez G, Delmaire C, Dujardin K, Dellacherie D, Brice A, Stevanin G, Strubi-Vuillaume I, Dürr A, Sablonnière B.

Brain. 2014 Oct;137(Pt 10):2657-63. doi: 10.1093/brain/awu202. Epub 2014 Jul 28.

PubMed [citation]

PMID:: 25070513

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000195808.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000597502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris, SCV001519238.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002556705.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764933.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769210.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), SCV003920741.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV005043987.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS2_VS, PS4, PM2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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