Submissions for variant NM_021830.5(TWNK):c.1196A>G (p.Asn399Ser)

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Total submissions: 10

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001722090	SCV006559912	uncertain significance	not provided	2025-09-01	criteria provided, single submitter	clinical testing	TWNK: PM2, PM3:Supporting, PP3
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001105894	SCV005442092	uncertain significance	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	2024-12-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001722090	SCV002235458	pathogenic	not provided	2024-02-03	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 399 of the TWNK protein (p.Asn399Ser). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive TWNK-related conditions (PMID: 26970254, 28178980, 30799093, 31852434). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214185). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TWNK protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001105895	SCV001262910	uncertain significance	Autosomal recessive cerebellar ataxia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001105894	SCV001262909	uncertain significance	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000578276	SCV001262908	uncertain significance	Infantile onset spinocerebellar ataxia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001105893	SCV001262907	uncertain significance	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics Munich, TUM University Hospital	RCV000578276	SCV000680157	pathogenic	Infantile onset spinocerebellar ataxia	2017-09-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001722090	SCV000251220	likely pathogenic	not provided	2020-11-25	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28178980, 26970254, 26206283, 30799093, 31852434)
GeneReviews	RCV002515383	SCV003525965	not provided	Perrault syndrome		no classification provided	literature only

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