Submissions for variant NM_024753.5(TTC21B):c.2227G>A (p.Val743Ile)

gnomAD frequency: 0.00019  dbSNP: rs183367929

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000263172	SCV000417633	uncertain significance	Nephronophthisis 12	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.
Illumina Laboratory Services, Illumina	RCV000318231	SCV000417634	uncertain significance	Asphyxiating thoracic dystrophy 4	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.
GeneDx	RCV000756833	SCV000492402	likely benign	not provided	2020-09-28	criteria provided, single submitter	clinical testing
Invitae	RCV000634198	SCV000755501	likely benign	Jeune thoracic dystrophy; Nephronophthisis	2023-11-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756833	SCV000884763	uncertain significance	not provided	2017-10-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002521311	SCV003610303	uncertain significance	Inborn genetic diseases	2021-06-22	criteria provided, single submitter	clinical testing	The c.2227G>A (p.V743I) alteration is located in exon 17 (coding exon 17) of the TTC21B gene. This alteration results from a G to A substitution at nucleotide position 2227, causing the valine (V) at amino acid position 743 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003401352	SCV004102966	uncertain significance	TTC21B-related condition	2022-12-19	criteria provided, single submitter	clinical testing	The TTC21B c.2227G>A variant is predicted to result in the amino acid substitution p.Val743Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-166769119-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.