Submissions for variant NM_000360.4(TH):c.67G>A (p.Ala23Thr)

gnomAD frequency: 0.00028  dbSNP: rs201081519

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000513281	SCV000608576	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	TH: PM2, PM3:Supporting
Illumina Laboratory Services, Illumina	RCV001103470	SCV001260235	uncertain significance	Autosomal recessive DOPA responsive dystonia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001103470	SCV001416320	likely benign	Autosomal recessive DOPA responsive dystonia	2024-12-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001103470	SCV002792115	uncertain significance	Autosomal recessive DOPA responsive dystonia	2021-07-06	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000513281	SCV005191119	uncertain significance	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000513281	SCV001553859	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TH p.Ala23Thr variant was not identified in the literature but was identified in dbSNP (ID: rs201081519) and ClinVar (classified as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 66 of 280418 chromosomes at a frequency of 0.0002354 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 11 of 24894 chromosomes (freq: 0.000442), South Asian in 11 of 30610 chromosomes (freq: 0.000359), Other in 2 of 7176 chromosomes (freq: 0.000279), European (non-Finnish) in 35 of 127596 chromosomes (freq: 0.000274), Latino in 5 of 35382 chromosomes (freq: 0.000141), Ashkenazi Jewish in 1 of 10312 chromosomes (freq: 0.000097) and East Asian in 1 of 19908 chromosomes (freq: 0.00005), but was not observed in the European (Finnish) population. The p.Ala23 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.