Submissions for variant NM_007375.4(TARDBP):c.1055A>G (p.Asn352Ser)

dbSNP: rs80356734

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000993301	SCV001146151	pathogenic	not provided	2019-02-20	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/281796 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease, but in a single family. (p < 0.05)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851975	SCV002242980	pathogenic	Amyotrophic lateral sclerosis type 10; TARDBP-related frontotemporal dementia	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 352 of the TARDBP protein (p.Asn352Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18779421, 23327806, 24117534, 24237396). ClinVar contains an entry for this variant (Variation ID: 21468). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TARDBP function (PMID: 22406069, 24440310). This variant disrupts the p.Asn352 amino acid residue in TARDBP. Other variant(s) that disrupt this residue have been observed in individuals with TARDBP-related conditions (PMID: 20031275), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000020657	SCV002580412	likely pathogenic	Amyotrophic lateral sclerosis type 10	2021-10-11	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000020657	SCV002758560	pathogenic	Amyotrophic lateral sclerosis type 10	2022-08-24	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP2
CeGaT Center for Human Genetics Tuebingen	RCV000993301	SCV004184991	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, PP2, PS3:Supporting
GeneReviews	RCV000020657	SCV000041195	not provided	Amyotrophic lateral sclerosis type 10		no assertion provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000993301	SCV001929760	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000993301	SCV001967817	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754269	SCV005365263	pathogenic	TARDBP-related disorder	2024-08-09	no assertion criteria provided	clinical testing	The TARDBP c.1055A>G variant is predicted to result in the amino acid substitution p.Asn352Ser. This variant has been reported in multiple unrelated families and is causative for amyotrophic lateral sclerosis (Kühnlein et al. 2008. PubMed ID: 18779421; Budini et al. 2012. PubMed ID: 22406069; Watanabe et al. 2012. PubMed ID: 23235148; Czell et al. 2013. PubMed ID: 23327806; Homma et al. 2014. PubMed ID: 24117534). This variant has not been reported in a large population database, indicating this variant is rare. This variant is within the known TARDBP mutational hotspot and has also been consistently classified as pathogenic/likely pathogenic in ClinVar. This variant is interpreted as pathogenic.