Submissions for variant NM_001136193.2(FASTKD2):c.149A>G (p.Lys50Arg)

gnomAD frequency: 0.00289  dbSNP: rs141447598

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000442317	SCV000510732	uncertain significance	not provided	2016-10-25	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000442317	SCV000609021	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	FASTKD2: BP4, BS2
GeneDx	RCV000442317	SCV000728411	likely benign	not provided	2019-12-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25842392, 25842391, 25497598)
Invitae	RCV000442317	SCV001040143	likely benign	not provided	2024-01-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001136866	SCV001296740	uncertain significance	Cytochrome-c oxidase deficiency disease	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.
PreventionGenetics, part of Exact Sciences	RCV003912596	SCV004729514	likely benign	FASTKD2-related condition	2021-05-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mayo Clinic Laboratories, Mayo Clinic	RCV000442317	SCV000802777	uncertain significance	not provided	2016-02-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000442317	SCV001552474	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FASTKD2 p.Lys50Arg variant was identified in 1 of 70 proband chromosomes (frequency: 0.0143) from individuals with ataxia (Pyle_2014_PMID: 25497598). The variant was identified in dbSNP (ID: rs141447598) and ClinVar (classified as likely benign by GeneDx and Invitae, and as uncertain significance by Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics, CeGaT Praxis fuer Humangenetik Tuebingen, and Mayo Clinic). The variant was identified in control databases in 761 of 279634 chromosomes (2 homozygous) at a frequency of 0.002721 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 114 of 25062 chromosomes (freq: 0.004549), European (non-Finnish) in 535 of 128174 chromosomes (freq: 0.004174), Other in 23 of 7130 chromosomes (freq: 0.003226), Latino in 53 of 34698 chromosomes (freq: 0.001527), African in 17 of 24846 chromosomes (freq: 0.000684), South Asian in 15 of 29724 chromosomes (freq: 0.000505), Ashkenazi Jewish in 2 of 10180 chromosomes (freq: 0.000197), and East Asian in 2 of 19820 chromosomes (freq: 0.000101). The p.Lys50 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.