Submissions for variant NM_000540.3(RYR1):c.13867G>A (p.Asp4623Asn)

gnomAD frequency: 0.00002  dbSNP: rs547709829

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000524026	SCV000618039	uncertain significance	not provided	2017-10-24	criteria provided, single submitter	clinical testing	The D4623N variant has been reported previously in an individual with multiminicore disease; however the variant was inherited from an asymptomatic parent (Snoeck et al., 2015). This variant is observed in 2/30782 (0.006%) alleles from individuals of South Asian background, in large population cohorts (Lek et al., 2016). The D4623N variant is a a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV001136421	SCV001296256	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2017-08-14	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001136422	SCV001296257	uncertain significance	Central core myopathy	2017-08-14	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001136423	SCV001296258	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2017-08-14	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527589	SCV003488611	uncertain significance	RYR1-related disorder	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 4623 of the RYR1 protein (p.Asp4623Asn). This variant is present in population databases (rs547709829, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 449692). 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.
Revvity Omics, Revvity	RCV000524026	SCV003812543	uncertain significance	not provided	2019-06-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001136423	SCV004816249	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 4623 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it has been observed in individuals affected with other phenotypes (PMID: 25960145). This variant has been identified in 5/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767324	SCV005381791	uncertain significance	not specified	2024-08-26	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.13867G>A (p.Asp4623Asn) results in a conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.13867G>A has been reported in the literature in one individual affected with multiminicore disease and unaffected mom (example, Snoeck_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Multicore Myopathy With External Ophthalmoplegia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 449692). Based on the evidence outlined above, the variant was classified as uncertain significance.
3billion	RCV001136421	SCV005904513	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2023-06-02	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RYR1 related disorder (PMID: 25960145). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.