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

dbSNP: rs606231451

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000322616	SCV000330042	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	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)
Genetic Services Laboratory, University of Chicago	RCV000148344	SCV000597502	likely pathogenic	Spinocerebellar ataxia type 21	2017-06-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000322616	SCV001250212	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TMEM240: PS2:Very Strong, PM2
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000322616	SCV001446440	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000322616	SCV001450010	likely pathogenic	not provided	2018-03-28	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000148344	SCV001519238	pathogenic	Spinocerebellar ataxia type 21	2021-01-04	criteria provided, single submitter	research
Genetics and Molecular Pathology, SA Pathology	RCV000148344	SCV002556705	pathogenic	Spinocerebellar ataxia type 21	2022-07-05	criteria provided, single submitter	clinical testing	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)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000148344	SCV002764933	pathogenic	Spinocerebellar ataxia type 21	2021-05-31	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000148344	SCV002769210	pathogenic	Spinocerebellar ataxia type 21	2022-03-31	criteria provided, single submitter	clinical testing	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
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV000148344	SCV003920741	pathogenic	Spinocerebellar ataxia type 21	2023-04-27	criteria provided, single submitter	research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000148344	SCV005043987	pathogenic	Spinocerebellar ataxia type 21	2024-01-12	criteria provided, single submitter	clinical testing	PS2_VS, PS4, PM2
OMIM	RCV000148344	SCV000195808	pathogenic	Spinocerebellar ataxia type 21	2014-10-01	no assertion criteria provided	literature only