Submissions for variant NM_001077365.2(POMT1):c.697_699del (p.Asn233del)

gnomAD frequency: 0.00001  dbSNP: rs761863400

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000384984	SCV000477652	uncertain significance	Limb-girdle muscular dystrophy, recessive	2016-06-14	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000850366	SCV000992549	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K	2019-03-20	criteria provided, single submitter	research	ACMG codes: PM2; PM3; PM4; PP3; PP5; PM2
Invitae	RCV001861343	SCV002161308	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1; Walker-Warburg congenital muscular dystrophy	2021-09-01	criteria provided, single submitter	clinical testing	This variant, c.697_699del, results in the deletion of 1 amino acid(s) of the POMT1 protein (p.Asn233del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with POMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 365275). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470848	SCV002768638	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous in-frame deletion variant was identified, NM_007171.3(POMT1):c.697_699del in exon 8 of 20 of the POMT1 gene. The variant is predicted to result in an in-frame deletion of a single amino acid at position 233 of the protein NP_009102.3(POMT1):p.(Asn233del). The asparagine at this position has low conservation (100 vertebrates, UCSC), but is located within the PMT functional domain. The variant is present in the gnomAD population database at a frequency of #% (0.0008% (2 heterozygotes; 0 homozygotes). The variant has been previously reported as a VUS (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.
PreventionGenetics, part of Exact Sciences	RCV004530476	SCV004113368	likely pathogenic	POMT1-related disorder	2023-02-15	criteria provided, single submitter	clinical testing	The POMT1 c.697_699delAAT variant is predicted to result in an in-frame deletion (p.Asn233del). The c.697_699delAAT nucleotides also reside at the end of exon 8 in alternative biologically relevant POMT1 transcripts (eg. NM_001077365.2) and deletion of these nucleotides is predicted to result in defective splicing by several in silico programs (Alamut Visual Plus v1.6.1). This variant was reported in the compound heterozygous state in an individual with a POMT1-related disorder (Table S2 - Bowling et al 2022. PubMed ID: 34930662). At PreventionGenetics, we have observed the c.697_699delAAT variant with a loss-of-function variant in POMT1 in a patient with suspected dystroglycanopathy (internal data). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-134385380-CAAT-C). This variant is interpreted as likely pathogenic.
GeneDx	RCV003441850	SCV004170064	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing	Observed with a pathogenic variant on the opposite allele (in trans) in a hospitalized infant in published literature, although clinical information was not provided (Bowling et al., 2022); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 34930662)
Athena Diagnostics	RCV003441850	SCV004229900	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
Revvity Omics, Revvity	RCV003441850	SCV004236458	uncertain significance	not provided	2023-02-27	criteria provided, single submitter	clinical testing