Submissions for variant NM_001077365.2(POMT1):c.1087C>T (p.Gln363Ter)

gnomAD frequency: 0.00008  dbSNP: rs200056620

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081477	SCV000225644	pathogenic	not provided	2014-11-04	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000081477	SCV000280652	pathogenic	not provided	2015-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000081477	SCV000329730	pathogenic	not provided	2023-12-29	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28116189, 30454682, 12369018, 31311558)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578428	SCV000680345	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1	2017-12-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686940	SCV000814481	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1; Walker-Warburg congenital muscular dystrophy	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln385*) in the POMT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMT1 are known to be pathogenic (PMID: 12369018, 15637732, 16575835). This variant is present in population databases (rs200056620, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with Walker-Warburg syndrome (PMID: 12369018, 28116189, 31311558). ClinVar contains an entry for this variant (Variation ID: 95452). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002288580	SCV002581357	pathogenic	Limb-girdle muscular dystrophy due to POMK deficiency	2022-05-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498428	SCV002813886	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1	2022-01-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460755	SCV004206041	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	2023-11-28	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002498428	SCV005044071	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1	2023-02-09	criteria provided, single submitter	clinical testing	The inherited c.1087C>T, p.(Gln363Ter) variant (annotation based on MANE Select transcript NM_001077365.2) identified in the POMT1 gene is a nonsense variant predicted to lead to the premature termination of the protein at amino acid 363/726 (exon 12/20) and is expected to lead to the loss of protein function via nonsense mediated decay. This variant is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) with highest allele frequency of 4.53e-5 (BRAVO-TOPMed, 12 heterozygotes, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. The c.1087C>T, p.(Gln363Ter) variant is reported in ClinVar as Pathogenic (VarID:95452; 2 stars, 7 submissions, no conflicts) and has been reported in individuals in the literature with Walker-Warburg syndrome in both homozygous state [PMID:12369018], and in compound heterozygosity with a second pathogenic variant [PMID:15522202] (reported as c.1153C>T (p.(Gln385Ter) as annotated from transcript NM_007171). Given its deleterious nature, low frequency in population databases, and observation in affected individuals in the literature in homozygosity and in compound heterozygosity with a second pathogenic variant, the inherited c.1087C>T, p.(Gln363Ter) variant is reported as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689449	SCV005185435	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-05-07	criteria provided, single submitter	clinical testing	Variant summary: POMT1 c.1153C>T (p.Gln385X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.6e-05 in 249572 control chromosomes. c.1153C>T has been reported in the literature in homozygous twins affected with Walker-Warburg syndrome (e.g. Beltran-Valero_2002). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12369018). ClinVar contains an entry for this variant (Variation ID: 95452). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003460755	SCV005400385	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A1 (MIM#236670), muscular dystrophy-dystroglycanopathy (congenital with intellectual development), type B, 1 (MIM#613155) and muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 (MIM#609308). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypic spectrum ranges from the severe Walker-Warburg syndrome (WWS) to milder forms of limb girdle muscular dystrophy (LGMD) (PMID: 31311558; OMIM). (I) 0202 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction), but is located in an exon that may undergo alternative splicing. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (110 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in ClinVar. It has also been reported in three affected fetuses with prenatal onset Walker-Warburg syndrome (PMID: 31311558). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign