NM_001447.3(FAT2):c.10946G>A (p.Arg3649Gln) AND Spinocerebellar ataxia 45

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 15, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000515512.1

Allele description [Variation Report for NM_001447.3(FAT2):c.10946G>A (p.Arg3649Gln)]

NM_001447.3(FAT2):c.10946G>A (p.Arg3649Gln)

Genes:

FAT2:FAT atypical cadherin 2 [Gene - OMIM - HGNC]
SLC36A1:solute carrier family 36 member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q33.1

Genomic location:

Preferred name:

NM_001447.3(FAT2):c.10946G>A (p.Arg3649Gln)

HGVS:

NC_000005.10:g.151521647C>T
NG_046979.1:g.135494G>A
NM_001447.3:c.10946G>AMANE SELECT
NP_001438.1:p.Arg3649Gln
NP_001438.1:p.Arg3649Gln
NC_000005.9:g.150901208C>T
NM_001447.2:c.10946G>A

Protein change:

R3649Q; ARG3649GLN

Links:

OMIM: 604269.0002; dbSNP: rs201335279

Molecular consequence:

NM_001447.3:c.10946G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Spinocerebellar ataxia 45
Identifiers:: MONDO: MONDO:0033480; MedGen: C4540400; OMIM: 617769

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000611608	OMIM	no assertion criteria provided	Pathogenic (Nov 16, 2017)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000883164	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 15, 2018)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 29053796, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000611608

OMIM

no assertion criteria provided

Pathogenic
(Nov 16, 2017)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000883164

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 15, 2018)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia.

Nibbeling EAR, Duarri A, Verschuuren-Bemelmans CC, Fokkens MR, Karjalainen JM, Smeets CJLM, de Boer-Bergsma JJ, van der Vries G, Dooijes D, Bampi GB, van Diemen C, Brunt E, Ippel E, Kremer B, Vlak M, Adir N, Wijmenga C, van de Warrenburg BPC, Franke L, Sinke RJ, Verbeek DS.

Brain. 2017 Nov 1;140(11):2860-2878. doi: 10.1093/brain/awx251.

PubMed [citation]

PMID:: 29053796

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000611608.1

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

Description

In a man (case DNA056251) with spinocerebellar ataxia-45 (SCA45; 617769), Nibbeling et al. (2017) identified a heterozygous c.10946G-A transition (chr5.150901208, GRCh37) in the FAT2 gene, resulting in an arg3649-to-gln (R3649Q) substitution at a highly conserved residue in the linker between the last cadherin repeat and the laminin A-G motif. The mutation was found by exome sequencing using a gene panel and confirmed by Sanger sequencing.

#	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 SIB Swiss Institute of Bioinformatics, SCV000883164.1

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

Description

This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Spinocerebellar ataxia 45, autosomal dominant. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product (https://www.ncbi.nlm.nih.gov/pubmed/29053796).

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

Last Updated: May 16, 2025

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