Submissions for variant NM_017739.4(POMGNT1):c.550C>T (p.His184Tyr)

gnomAD frequency: 0.00005  dbSNP: rs746638187

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531957	SCV000649972	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 184 of the POMGNT1 protein (p.His184Tyr). This variant is present in population databases (rs746638187, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of muscle-eye-brain disease (PMID: 30937090). ClinVar contains an entry for this variant (Variation ID: 471407). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago	RCV001821571	SCV002070484	uncertain significance	not specified	2017-10-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002261116	SCV002542175	uncertain significance	not provided	2021-05-18	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002530070	SCV003761194	uncertain significance	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The p.His184Tyr variant in POMGNT1 has been reported in one individual with muscular dystrophy-dystroglycanopathy (PMID: 30937090), and has also been identified in 0.009% (12/128998) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs746638187). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. The variant has also been reported in ClinVar (Variation ID#: 471407) as a variant of uncertain significance by Invitae, Mayo Clinic Laboratories, Genetic Services Laboratory (University of Chicago), Lupski Lab (Baylor-Hopkins CMG, Baylor College of Medicine), and Natera, Inc. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.His184Tyr variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting (Richards 2015).
Revvity Omics, Revvity	RCV002261116	SCV003811732	uncertain significance	not provided	2020-08-18	criteria provided, single submitter	clinical testing
GeneDx	RCV002261116	SCV005326089	uncertain significance	not provided	2024-02-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in several individuals with clinical findings of POMGNT1-related disorders in published literature (PMID: 36964972, 30937090, 31230720); This variant is associated with the following publications: (PMID: 34426522, 36964972, 31230720, 30937090)
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760586	SCV005368282	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2024-08-13	criteria provided, single submitter	clinical testing	Criteria applied: PM3,PM2_SUP
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV001007817	SCV001167508	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2O		no assertion criteria provided	research
Natera, Inc.	RCV001275753	SCV001461203	uncertain significance	Muscle eye brain disease	2020-09-16	no assertion criteria provided	clinical testing