Submissions for variant NM_182961.4(SYNE1):c.4000C>G (p.Arg1334Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002675475	SCV002972711	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-09-13	criteria provided, single submitter	clinical testing	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. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1341 of the SYNE1 protein (p.Arg1341Gly).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786731	SCV005399356	uncertain significance	Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. Multiple NMD-predicted variants have previously been reported in this gene whilst missense variants have been shown to have loss of function effects (ClinVar; PMID 30573412). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Missense variants have also been shown to have dominant-negative effects (PMID 17761684). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a glycine (exon 31). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (13 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and moderate conservation with a major amino acid change. (N) 0600 - Variant is located in an annotated domain or motif (SMC prok B super family; NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign