Submissions for variant NM_001025356.3(ANO6):c.1387-1G>T

gnomAD frequency: 0.00011  dbSNP: rs374664255

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521649	SCV000617849	pathogenic	not provided	2020-12-17	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 21107324)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000521649	SCV002213181	pathogenic	not provided	2022-05-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 12 of the ANO6 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs374664255, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with Scott disease and/or Scott syndrome (PMID: 21107324). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449565). Studies have shown that disruption of this splice site results in skipping of exon 13 and introduces a premature termination codon (PMID: 21107324). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001706657	SCV003922758	pathogenic	SCOTT SYNDROME	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: ANO6 c.1387-1G>T 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. This effect on splicing was experimentally confirmed: cDNA sequencing of a homozygous patient showed skipping of exon 13 (Suzuki_2010). The variant allele was found at a frequency of 7.2e-05 in 251160 control chromosomes (gnomAD). c.1387-1G>T has been reported in the literature in at least one homozygous individual affected with Scott syndrome (Suzuki_2010). These data indicate that the variant may be associated with disease. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003419904	SCV004115263	pathogenic	ANO6-related disorder	2022-11-14	criteria provided, single submitter	clinical testing	The ANO6 c.1387-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the homozygous state in an individual with Scott syndrome (Figure 4 in Suzuki et al 2010. PubMed ID: 21107324). Splicing studies found this variant leads to skipping of the exon which is predicted to result in a frameshift and premature truncation of the protein (Figure 4 in Suzuki et al 2010. PubMed ID: 21107324). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-45795577-G-T). Variants that disrupt the consensus splice acceptor site in ANO6 (previously known as TMEM16F) are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV001706657	SCV000045010	pathogenic	SCOTT SYNDROME	2010-12-09	no assertion criteria provided	literature only