Submissions for variant NM_021942.6(TRAPPC11):c.1287+5G>A

gnomAD frequency: 0.00004  dbSNP: rs397509418

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414573	SCV000491339	pathogenic	not provided	2022-02-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate disruption of the Golgi apparatus architecture and impaired the binding ability of TRAPPC11 to TRAPPC2 (Bogershausen et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 26322222, 24843229, 23830518, 29158550, 31575891, 32528171, 34426522, 25697177)
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000054409	SCV000586713	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type R18	2017-08-01	criteria provided, single submitter	clinical testing	Variant previously described as pathogenic and as a founder mutation was identified in homozygous tate in a patient with strabismus, mildly elevated CK, moderate ID, movement disorder. Both parent were heterozygous carriers.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000054409	SCV000680416	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type R18	2017-12-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000054409	SCV000893669	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type R18	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000054409	SCV001221302	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type R18	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the TRAPPC11 gene. It does not directly change the encoded amino acid sequence of the TRAPPC11 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs397509418, gnomAD 0.009%). This variant has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy and/or movement disorder and intellectual disability (PMID: 23830518, 29158550). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60511). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exons 11-12, but is expected to preserve the integrity of the reading-frame (PMID: 23830518). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000414573	SCV001249262	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001254697	SCV001430763	pathogenic	Muscular dystrophy, limb-girdle, autosomal recessive 23	2020-05-29	criteria provided, single submitter	research	The c.1287+5G>A variant in TRAPPC11 was identified by our study in 1 individual with limb girdle muscular dystrophy in the compound heterozygous state, along with another likely pathogenic variant. The variant in TRAPPC11 has been reported in at least 5 Syrian individuals with limb-girdle muscular dystrophy (PMID: 23830518, 31575891), segregated with disease in 3 affected relatives from 2 families (PMID: 23830518), and has been identified in 0.009% (12/129080) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397509418). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic/likely pathogenic by multiple submitters (Variation ID: 60511). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 23830518). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for limb-girdle muscular dystrophy in an autosomal recessive manner based on the predicted impact of the variant and multiple homozygous occurrences in individuals with limb-girdle muscular dystrophy, as well as co-segregations with disease in multiple affected family members in two families. ACMG/AMP Criteria applied: PP1_strong, PM2, PS3_moderate, PP3, PM3 (Richards 2015).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000414573	SCV001447224	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000054409	SCV002022412	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type R18	2021-11-01	criteria provided, single submitter	clinical testing
OMIM	RCV000054409	SCV000082886	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type R18	2013-07-11	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000414573	SCV001808816	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000414573	SCV001931606	likely pathogenic	not provided		no assertion criteria provided	clinical testing