Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017739.4(POMGNT1):c.1350_1354delCTGGG(p.Trp451AlafsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G450G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
POMGNT1 (HGNC:19139): (protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-)) This gene encodes a type II transmembrane protein that resides in the Golgi apparatus. It participates in O-mannosyl glycosylation and is specific for alpha linked terminal mannose. Mutations in this gene may be associated with muscle-eye-brain disease and several congenital muscular dystrophies. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Feb 2014]
TSPAN1 (HGNC:20657): (tetraspanin 1) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. [provided by RefSeq, Jul 2008]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-46192366-ACCCAG-A is Pathogenic according to our data. Variant chr1-46192366-ACCCAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 56581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46192366-ACCCAG-A is described in Lovd as [Likely_pathogenic]. Variant chr1-46192366-ACCCAG-A is described in Lovd as [Pathogenic].
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
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Oct 28, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:1
Nov 10, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change creates a premature translational stop signal (p.Trp451Alafs*11) in the POMGNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with POMGNT1-related conditions (PMID: 17906881, 32404165). ClinVar contains an entry for this variant (Variation ID: 56581). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Jul 19, 2018
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Significance: Pathogenic
Review Status: criteria provided, single submitter