Submissions for variant NM_213599.3(ANO5):c.749A>G (p.Tyr250Cys)

gnomAD frequency: 0.00006  dbSNP: rs781734224

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000364651	SCV000339522	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000663412	SCV000786700	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2L		criteria provided, single submitter	research	The heterozygous p.Tyr250Cys variant was identified in the compound heterozygous state by our study in one individual with Limb-Girdle Muscular Dystrophy. The p.Tyr250Cys variant has been reported as a VUS in 2 individuals in ClinVar (ID: 286191). It has also been identified in 0.01% (1/10378) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). The Tyrosine (Tyr) at position 250 is not conserved in mammals or evolutionary distant species, raising the possibility/supporting that a change at this position may be tolerated. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Tyr250Cys variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792580	SCV000931885	uncertain significance	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 250 of the ANO5 protein (p.Tyr250Cys). This variant is present in population databases (rs781734224, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of ANO5-related conditions (PMID: 32528171; internal data). ClinVar contains an entry for this variant (Variation ID: 286191). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ANO5 protein function with a positive predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689704	SCV005184695	uncertain significance	not specified	2024-05-14	criteria provided, single submitter	clinical testing	Variant summary: ANO5 c.749A>G (p.Tyr250Cys) results in a non-conservative amino acid change located in the dimerisation domain (IPR032394) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250906 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.749A>G has been reported in the literature in multiple individuals affected with (suspected) Muscular Dystrophy(e.g. Nallamilli_2018, Topf_2020, Zidkova_2023). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30564623, 32528171, 37526466). ClinVar contains an entry for this variant (Variation ID: 286191). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV000364651	SCV005628453	likely pathogenic	not provided	2024-07-11	criteria provided, single submitter	clinical testing	Has been reported in patients with features of limb-girdle muscular dystrophy in the published literature (PMID: 37526466, 32528171); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37526466, 32528171, 30564623)