ClinVar Miner

Submissions for variant NM_001375380.1(EBF3):c.422A>G (p.Tyr141Cys)

dbSNP: rs1057519519
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000817610 SCV000958179 pathogenic not provided 2021-09-02 criteria provided, single submitter clinical testing
Mendelics RCV000417002 SCV001138184 pathogenic Hypotonia, ataxia, and delayed development syndrome 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001266398 SCV001444572 likely pathogenic Inborn genetic diseases 2016-12-28 criteria provided, single submitter clinical testing
Suma Genomics RCV000417002 SCV002543783 pathogenic Hypotonia, ataxia, and delayed development syndrome criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000417002 SCV002549842 pathogenic Hypotonia, ataxia, and delayed development syndrome 2022-06-28 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS3, PS2_MOD, PS4_MOD, PM2_SUP, PP2, PP3
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000417002 SCV003761216 likely pathogenic Hypotonia, ataxia, and delayed development syndrome 2023-01-24 criteria provided, single submitter curation The heterozygous p.Tyr141Cys variant in EBF3 was identified by our study in one individual with hypotonia, global developmental delay, and poor gross motor coordination. Trio exome analysis showed this variant to be de novo. The p.Tyr141Cys variant in EBF3 has been previously reported in one individual with hypotonia, ataxia, and delayed development syndrome (HADDS). This variant was found to be de novo in this individual with confirmed paternity and maternity (PMID: 28017373). This variant has also been reported in ClinVar (Variation ID:375497) and has been interpreted as pathogenic by Mendelics, Invitae, Suma Genomics, Leipzig Medical Center Institute of Human Genetics, and OMIM, and as likely pathogenic by Ambry Genetics. This variant was absent from large population studies. The number of missense variants reported in EBF3 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In vitro functional studies provide some evidence that the p.Tyr141Cys variant may impact protein function (PMID: 28017373). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant hypotonia, ataxia, and delayed development syndrome (HADDS). ACMG/AMP Criteria applied: PS2, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP2 (Richards 2015).
OMIM RCV000417002 SCV000494486 pathogenic Hypotonia, ataxia, and delayed development syndrome 2017-02-07 no assertion criteria provided literature only

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