Submissions for variant NM_213599.2(ANO5):c.1664G>T (p.Ser555Ile) (rs375014127)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000498271	SCV000339889	uncertain significance	not provided	2018-08-30	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000414780	SCV000492898	likely pathogenic	Myopathy	2014-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000498271	SCV000589776	uncertain significance	not provided	2018-11-07	criteria provided, single submitter	clinical testing	The S555I variant was previously reported in an individual with LGMD, who harbored an additional pathogenic variant on the other ANO5 allele (in trans); however, functional studies where not performed (Kuhn et al., 2016). The S555I variant is observed in 25/126546 (0.02%) alleles from individuals of European background (Lek et al., 2016). The S555I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000627020	SCV000747723	pathogenic	Elevated serum creatine phosphokinase; Distal muscle weakness; Fatty replacement of skeletal muscle	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV001068054	SCV001233143	uncertain significance	Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L	2019-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine with isoleucine at codon 555 of the ANO5 protein (p.Ser555Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs375014127, ExAC 0.02%). This variant has been observed in combination with other ANO5 variants in individuals with limb-girdle muscular dystrophy (PMID: 25891276, 26886200, 27911336, 30564623). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 286450). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001198354	SCV001369258	pathogenic	Gnathodiaphyseal dysplasia	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP4,PP5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000498271	SCV001446406	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing