Submissions for variant NM_213599.3(ANO5):c.41-1G>A

gnomAD frequency: 0.00006  dbSNP: rs398124625

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082852	SCV000227601	pathogenic	not provided	2016-09-14	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000176019	SCV000255644	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2013-11-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000082852	SCV000329926	pathogenic	not provided	2018-07-27	criteria provided, single submitter	clinical testing	The c.41-1G>A pathogenic variant in the ANO5 gene has been reported previously in the compound heterozygous state with another pathogenic variant in an individual with limb-girdle muscular dystrophy (van der Kooi et al., 2013). This splice site variant destroys the canonical splice acceptor site in intron 1. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.41-1G>A variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.41-1G>A as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645359	SCV000767103	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2024-08-15	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 of the ANO5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276, 30919934). This variant is present in population databases (rs398124625, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with limb-girdle muscular dystrophy and hyperCKemia and periodic loss of ambulation (PMID: 23607914; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 96685). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000082852	SCV001448042	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000082852	SCV001747582	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000082852	SCV002017070	pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing