ClinVar Miner

Submissions for variant NM_013382.7(POMT2):c.924-2A>C

dbSNP: rs886044256
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523465 SCV000617439 pathogenic not provided 2016-06-08 criteria provided, single submitter clinical testing The c.924-2 A>C pathogenic splice site variant has been previously reported as a homozygous variant in three fetus' with congenital hydrocephalus in one consanguineous family (Abumansour et al., 2015). This variant destroys the canonical splice acceptor site of intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.924-2 A>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.924-2 A>C as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000822848 SCV000963667 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2; Autosomal recessive limb-girdle muscular dystrophy type 2N 2021-03-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POMT2 are known to be pathogenic (PMID: 15894594). Disruption of this splice site has been observed in several individuals affected with POMT2-related Walker-Warburg Syndrome or POMT2-related lissencephaly (PMID: 18752264, 26495167, 17559086). ClinVar contains an entry for this variant (Variation ID: 449378). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 of the POMT2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Baylor Genetics RCV003476218 SCV004204126 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 2022-05-13 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV003476218 SCV004808098 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 2024-03-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586753 SCV005076970 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2024-04-08 criteria provided, single submitter clinical testing Variant summary: POMT2 c.924-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246094 control chromosomes (gnomAD). c.924-2A>C has been reported in the literature in individuals affected with Walker-Warburg Syndrome (Manzini_2008, Abumansour_2015). These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 449378). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000822848 SCV005635518 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2; Autosomal recessive limb-girdle muscular dystrophy type 2N 2024-04-12 criteria provided, single submitter clinical testing

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