Submissions for variant NM_005055.5(RAPSN):c.1066G>A (p.Val356Met)

gnomAD frequency: 0.00005  dbSNP: rs570140663

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000404405	SCV000372439	uncertain significance	Congenital myasthenic syndrome 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000307953	SCV000372440	uncertain significance	Fetal akinesia deformation sequence 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706275	SCV000835315	uncertain significance	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 356 of the RAPSN protein (p.Val356Met). This variant is present in population databases (rs570140663, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAPSN-related conditions. ClinVar contains an entry for this variant (Variation ID: 304970). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAPSN protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV002487360	SCV002776170	uncertain significance	Congenital myasthenic syndrome 11; Fetal akinesia deformation sequence 2	2022-01-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003243062	SCV003941465	uncertain significance	Inborn genetic diseases	2023-05-23	criteria provided, single submitter	clinical testing	The c.1066G>A (p.V356M) alteration is located in exon 7 (coding exon 7) of the RAPSN gene. This alteration results from a G to A substitution at nucleotide position 1066, causing the valine (V) at amino acid position 356 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV003488516	SCV004236550	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001274400	SCV001458527	uncertain significance	Congenital myasthenic syndrome	2020-04-13	no assertion criteria provided	clinical testing