Submissions for variant NM_017739.4(POMGNT1):c.351del (p.Thr118fs)

dbSNP: rs386834028

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853065	SCV002233037	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2021-08-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56598). This variant is also known as c.350delC (p.T117fsX26). This premature translational stop signal has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 19299310). This variant is present in population databases (rs386834028, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Thr118Argfs*26) 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).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002514266	SCV003761201	pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The p.Thr118fs variant in POMGNT1 has been reported in at least 2 individuals with muscular dystrophy-dystroglycanopathy (PMID: 22554691, 192993101), and has been identified in 0.0009% (1/113672) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1339563119). 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. This variant has also been reported in ClinVar (Variation ID#:56598) and has been interpreted as pathogenic by Invitae and the Juha Muilu Group (Institute for Molecular Medicine Finland (FIMM)). Of the two affected individuals, two were compound heterozygotes who carried a pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Thr118fs variant is pathogenic (ClinVarID: 56593; PMID: 22554691, 19299310). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 118 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. In summary, this variant meets criteria to be classified as pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong (Richards 2015).
Revvity Omics, Revvity	RCV003137592	SCV003818523	pathogenic	not provided	2022-06-08	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050011	SCV000082420	probable-pathogenic	Muscle eye brain disease		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.