Submissions for variant NM_001371986.1(UNC80):c.1806G>C (p.Gln602His)

gnomAD frequency: 0.00163  dbSNP: rs200473652

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000258922	SCV000328693	likely pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 2	2016-10-13	criteria provided, single submitter	research
Invitae	RCV000963427	SCV001110579	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000258922	SCV001136157	uncertain significance	Hypotonia, infantile, with psychomotor retardation and characteristic facies 2	2019-05-28	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001252621	SCV001437903	likely pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002274004	SCV002559059	likely pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000258922	SCV002768725	likely benign	Hypotonia, infantile, with psychomotor retardation and characteristic facies 2	2022-09-02	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_032504.1(UNC80):c.1806G>C, has been identified in exon 12 of 64 of the UNC80 gene. The variant is predicted to result in a minor amino acid change from glutamine to histidine at position 602 of the protein (NP_115893.1(UNC80):p.(Gln602His)). The glutamine residue at this position has high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.14% (271 heterozygotes, 1 homozygote). The variant has been previously described as likely pathogenic (ClinVar, Decipher) and also VUS (EGL Genetics). Based on the information available at the time of curation, this variant has been classified as LIKELY BENIGN.
Ambry Genetics	RCV002518797	SCV003617325	likely benign	Inborn genetic diseases	2021-03-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000258922	SCV003828044	uncertain significance	Hypotonia, infantile, with psychomotor retardation and characteristic facies 2	2019-08-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535244	SCV004724952	likely benign	UNC80-related disorder	2021-01-18	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987484	SCV004804097	likely benign	not specified	2024-01-03	criteria provided, single submitter	clinical testing	Variant summary: UNC80 c.1806G>C (p.Gln602His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 158532 control chromosomes in the gnomAD database, including 1 homozygotes. c.1806G>C has been reported in the literature in individuals with neurodevelopmental disorders or unaffected individuals. These report(s) do not provide unequivocal conclusions about association of the variant with Infantile Hypotonia With Psychomotor Retardation And Characteristic Facies 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31589614, 29158550). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252621	SCV001428382	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing