Submissions for variant NM_213599.3(ANO5):c.2503_2505del (p.Phe835del)

dbSNP: rs794727350

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	RCV004998373	SCV005620282	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2025-01-07	reviewed by expert panel	curation	The NM_213599.3: c.2503_2505del variant in ANO5 is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region, p.(Phe835del) (PM4). This variant has been detected with a pathogenic ANO5 variant in at least four individuals with LGMD, including confirmed in trans in one patient (c.191dup, 1 pt, ClinVar SCV000767093.6 internal data communication) and in unknown phase in two patients (c.2018A>G p.(Tyr673Cys), 0.5 pts, ClinVar SCV000767093.6 internal data communication; c.191dup, 0.5 pts, ClinVar SCV000574876.19 internal data communication) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). The filtering allele frequency of this variant is 0.000017531 (the upper threshold of the 95% CI of 12/1109046 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the ClinGen LGMD threshold ≤0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM4, PM3_Strong, PP4, PM2_Supporting.
Eurofins Ntd Llc (ga)	RCV000176243	SCV000331763	likely pathogenic	not provided	2017-04-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000176243	SCV000574876	uncertain significance	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645349	SCV000767093	likely pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2024-05-20	criteria provided, single submitter	clinical testing	This variant, c.2503_2505del, results in the deletion of 1 amino acid(s) of the ANO5 protein (p.Phe835del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs765340468, gnomAD 0.004%). This variant has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (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: 195634). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.