ClinVar Miner

Submissions for variant NM_017739.3(POMGNT1):c.1895+1G>T (rs386834024)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000050006 SCV000220292 likely pathogenic Muscle eye brain disease 2014-05-02 criteria provided, single submitter literature only
GeneDx RCV000490077 SCV000577451 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing The c.1895+1 G>T pathogenic variant in the POMGNT1 gene has been previously reported in individuals with POMGNT1-related disorders who harbor an additional POMGNT1 variant (Diesen et al., 2004; Devisme et al., 2012; Saredi et al., 2012). The c.1895+1 G>T variant destroys the canonical splice donor site in intron 21. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1895+1 G>T variant is observed in 8/64418 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Illumina Clinical Services Laboratory,Illumina RCV000366136 SCV000357980 likely pathogenic Congenital Muscular Dystrophy, alpha-dystroglycan related 2016-06-14 criteria provided, single submitter clinical testing The c.1895+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in at least four studies in which it was found in four patients with alpha dystroglycan-related congenital muscular dystrophy, including in a compound heterozygous state in three patients with muscle-eye-brain disease and in one patient with cobblestone lissencephaly (Diesen et al. 2004; Mercuri et al. 2009; Saredi et al. 2012; Devisme et al. 2012). The variant was absent from at least 125 control individuals but is reported at a frequency of 0.00047 in the European (Non-Finnish) population of the Exome Aggregation Consortium. RT-PCR experiments demonstrated that the variant affects splicing with retention of the intron between exons 21 and 22 (Saredi et al. 2012). Due to the potential impact of splice donor variants and the evidence from the literature, the c.1895+1G>T variant is classified as likely pathogenic for alpha dystroglycan-related congenital muscular dystrophy.
Illumina Clinical Services Laboratory,Illumina RCV000394027 SCV000357981 uncertain significance Limb-Girdle Muscular Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778243 SCV000914412 pathogenic POMGNT1-Related Disorders 2018-05-03 criteria provided, single submitter clinical testing The POMGNT1 c.1895+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in at least four studies in which it is found in a compound heterozygous state in three individuals with muscle-eye-brain disease and in one individual with cobblestone lissencephaly (Diesen et al. 2004; Mercuri et al. 2009; Saredi et al. 2012; Devisme et al. 2012). The variant was absent from at least 125 control individuals and is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR experiments demonstrated that the variant affects splicing with retention of the intron between exons 21 and 22 (Saredi et al. 2012). Due to the potential impact of splice donor variants and the evidence from the literature, the c.1895+1G>T variant is classified as pathogenic for POMGNT1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000704718 SCV000833678 likely pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C3; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B3 2018-05-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 21) of the POMGNT1 gene. This variant is present in population databases (rs386834024, ExAC 0.05%). This variant has been reported in individuals affected with alpha-dystroglycanopathies, including muscle-eye-brain disease (PMID: 15466003, 22554691, 28424332). It is also called chr 1:46,655,129C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 56593). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant results in the inclusion of part of intron 21 in the final spliced transcript, and results in reduced protein expression (PMID: 22554691, 28424332). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050006 SCV000082415 probable-pathogenic Muscle eye brain disease no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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