Submissions for variant NM_182961.4(SYNE1):c.24635G>A (p.Arg8212His)

gnomAD frequency: 0.00008  dbSNP: rs766462111

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593212	SCV000704287	uncertain significance	not provided	2016-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000593212	SCV001988658	uncertain significance	not provided	2021-04-19	criteria provided, single submitter	clinical testing	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: 19944109)
Invitae	RCV001867945	SCV002166082	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 8141 of the SYNE1 protein (p.Arg8141His). This variant is present in population databases (rs766462111, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 19944109). This variant is also known as R374H. ClinVar contains an entry for this variant (Variation ID: 499003). 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: "Possibly 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.
Revvity Omics, Revvity	RCV000593212	SCV003822780	uncertain significance	not provided	2021-10-06	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000593212	SCV004229274	uncertain significance	not provided	2022-10-11	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant is also reported in the literature as R374H. There was not enough information identified regarding segregation with disease in families to be useful in characterizing this variant. Computational tools disagree on the variant's effect on normal protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987615	SCV004804163	uncertain significance	not specified	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: SYNE1 c.24422G>A (p.Arg8141His) results in a non-conservative amino acid change in the encoded protein sequence. Two of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 245868 control chromosomes. c.24422G>A has been reported in the literature in at-least one individual affected with dilated cardiomyopathy requiring cardiac transplantation (example, Puckelwartz_2010). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, fibroblasts from the individual carrying this variant had increased expression of nesprin-1 and lamins A and C (Puckelwartz_2010). The following publication have been ascertained in the context of this evaluation (PMID: 21496632). ClinVar contains an entry for this variant (Variation ID: 499003, all VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.