Submissions for variant NM_000540.3(RYR1):c.13142C>G (p.Ala4381Gly)

gnomAD frequency: 0.00001  dbSNP: rs794727983

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180732	SCV000233216	uncertain significance	not provided	2015-01-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056937	SCV001221404	uncertain significance	RYR1-related disorder	2022-04-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 4381 of the RYR1 protein (p.Ala4381Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 199212). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 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.
Illumina Laboratory Services, Illumina	RCV001131928	SCV001291572	uncertain significance	Central core myopathy	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	RCV001131929	SCV001291573	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	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	RCV001131930	SCV001291574	uncertain significance	Malignant hyperthermia, susceptibility to, 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.
Ambry Genetics	RCV004020180	SCV004945807	uncertain significance	Inborn genetic diseases	2023-11-13	criteria provided, single submitter	clinical testing	The c.13142C>G (p.A4381G) alteration is located in exon 91 (coding exon 91) of the RYR1 gene. This alteration results from a C to G substitution at nucleotide position 13142, causing the alanine (A) at amino acid position 4381 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000180732	SCV001553353	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RYR1 p.Ala4376Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs794727983) and ClinVar (classified as a VUS by EGL Genetics Diagnostics). The variant was identified in control databases in 1 of 102912 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 1 of 38400 chromosomes (freq: 0.000026), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Ala4376 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV001056937	SCV005361579	uncertain significance	RYR1-related disorder	2024-06-04	no assertion criteria provided	clinical testing	The RYR1 c.13142C>G variant is predicted to result in the amino acid substitution p.Ala4381Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.