Submissions for variant NM_006088.6(TUBB4B):c.1171C>T (p.Arg391Cys)

dbSNP: rs1554786802

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000584738	SCV000883192	likely pathogenic	Leber congenital amaurosis with early-onset deafness	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for Leber congenital amaurosis with early-onset deafness, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29198720). PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29198720). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
GeneDx	RCV001755979	SCV001985785	pathogenic	not provided	2025-01-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect that results in diminished microtubule depolarization kinetics resulting in decreased microtubule growth rate (PMID: 29198720); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32681585, 29198720, 35240325, 36460718, 34021019)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000584738	SCV004814129	pathogenic	Leber congenital amaurosis with early-onset deafness	2024-04-15	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000584738	SCV005416281	pathogenic	Leber congenital amaurosis with early-onset deafness		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Supporting+PP4+PP1+PM6_Supporting+PM5+PP2+PP3_Moderate
OMIM	RCV000584738	SCV000692454	pathogenic	Leber congenital amaurosis with early-onset deafness	2018-02-16	no assertion criteria provided	literature only
Department of Medical Genetics, University of Pecs	RCV000584738	SCV002064316	likely pathogenic	Leber congenital amaurosis with early-onset deafness	2022-01-10	no assertion criteria provided	clinical testing	TUBB4B c.1171 C>T variant results in arginine to cysteine amino acid change at 390 position. Classification of the variant according to the ACMG guidelines provide moderate/strong evidence of pathogenicity. This variant has been reported in a Danish boy by Luscan et al (PMID: 29198720). Besides, this variant was observed in three members of a Hungarian family with Leber congenital amaurosis with early-onset deafness (LCAEOD) (under publication). The variant was assumed de novo with confirmation of only maternity (PM6). In vitro functional study of Luscan et al provide evidence that the variant has damaging effect on the gene product (PS3). The c.1171C>T variant affects the Arg390 amino acid residue where a different missense change (c.1172G>A) has been found to be pathogenic before (PM5). The c.1171C>T variant is absent from large general reference population and disease cohorts (1000Genomes, dbSNP, gnomAD: n>120 000 exomes and >15 000 genomes) (PM2). In silico prediction tools like PolyPhen, Provean and MutationTaster provide evidence that the c.1171C>T variant is a protein damaging, disease-causing variant (PP3). For these reasons, this variant was classified as a Likely Pathogenic variant for the autosomal dominant LCAEOD.