ClinVar Miner

Submissions for variant NM_007171.3(POMT1):c.2167dup (p.Asp723fs) (rs398124245)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081487 SCV000196875 pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing The c.2167dupG pathogenic variant in the POMT1 gene has been reported previously in trans with missense variants or a truncating variant in multiple individuals who presented with POMT1-related disorders (Beltran-Valero et al., 2002; Devisme et al., 2012; Wallace et al., 2014). The duplication causes a frameshift starting with codon Aspartic acid 723, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Asp723GlyfsX8. The c.2167dupG variant is predicted to cause loss of normal protein function through protein truncation, as the last 25 amino acids are replaced with 7 incorrect amino acids. This variant is observed in 13/10072 (0.13%) alleles from individuals of Ashkenazi Jewish background and in 47/274716 (0.017%) alleles globally in large population cohorts (Lek et al., 2016). We interpret c.2167dupG as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081487 SCV000227682 pathogenic not provided 2015-11-02 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000003411 SCV000538056 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 2015-07-24 criteria provided, single submitter clinical testing The c.2167dupG (p.Asp723Glyfs*730) frameshift variant in the POMT1 gene has been previously reported as homozygous (Wallace SE et al., 2014; van Reeuwijk J et al., 2006) as well as compound heterozygous (Beltrán-Valero de Bernabé D et al., 2002; Wallace SE et al., 2014) in patients who were diagnosed with WWS. Functional studies using a skin biopsy from a WWS patient, who was heterozygous for variant, showed that the protein's molecular weight and binding to the basement membrane ligand, laminin were all affected. Furthermore, immunofluorescence staining of a muscle biopsy from a patient, who was homozygous for this variant, showed almost complete absence of α-dystroglycan expression (Wallace SE et al., 2014). The frequency of this variant is absent in the 1000Genome and Exome Sequencing Project databases and is very low in ExAC (<0.1%). Finally, reputable clinical databases have classified this variant as Pathogenic. In summary, the evidence meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.
Invitae RCV000546035 SCV000649893 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C1; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B1; Walker-Warburg congenital muscular dystrophy 2018-12-05 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 20 of the POMT1 mRNA (c.2167dupG), causing a frameshift at codon 723. This creates a premature translational stop signal in the last exon of the POMT1 mRNA (p.Asp723Glyfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 25 amino acids of the POMT1 protein. This variant has been reported in the literature in the homozygous and compound heterozygous state with other pathogenic variants in individuals affected with Walker-Warburg syndrome and congenital muscular dystrophy (PMID: 12369018, 22323514, 17559086, 16575835, 24491487, 24304607). This variant is also known as c.2167InsG, c.2167_2168insG, and p.G722fs in the literature. ClinVar contains an entry for this variant (Variation ID: 3255). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778874 SCV000915272 pathogenic POMT1-Related Disorders 2018-08-22 criteria provided, single submitter clinical testing The POMT1 c.2167dupG (p.Asp723GlyfsTer8) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Asp723GlyfsTer8 variant, also referred to as c.2163_2164insG, has been reported in seven studies in a total of 19 patients with POMT1-related disorders, including in two in a homozygous state, 15 in a compound heterozygous state, and two in a heterozygous state in whom a second variant was not identified (Beltran-Valero de Bernabe et al. 2002; van Reeuwijk et al. 2006; Bouchet et al. 2007; Vajsar et al. 2008; Manzini et al. 2008; Devisme et al. 2012; Wallace et al. 2014). The majority of patients were affected with Walker-Warburg syndrome or, more generally, congenital muscular dystrophy. The p.Asp723GlyfsTer8 variant was absent from 298 controls and is reported at a frequency of 0.001291 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Asp723GlyfsTer8 variant is classified as pathogenic for POMT1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000003411 SCV000023569 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 2009-05-26 no assertion criteria provided literature only

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