Submissions for variant NM_000540.3(RYR1):c.9555G>C (p.Lys3185Asn)

gnomAD frequency: 0.00013  dbSNP: rs201080180

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804693	SCV000944614	uncertain significance	RYR1-related disorder	2022-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 3185 of the RYR1 protein (p.Lys3185Asn). This variant is present in population databases (rs201080180, gnomAD 0.03%). 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: 649704). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001310409	SCV001500196	uncertain significance	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487717	SCV002788326	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001310409	SCV003813059	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003258980	SCV003979730	uncertain significance	Inborn genetic diseases	2023-03-20	criteria provided, single submitter	clinical testing	The c.9555G>C (p.K3185N) alteration is located in exon 65 (coding exon 65) of the RYR1 gene. This alteration results from a G to C substitution at nucleotide position 9555, causing the lysine (K) at amino acid position 3185 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV003514415	SCV004358171	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 3185 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.6, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 32/184170 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	RCV004702434	SCV005203960	uncertain significance	not specified	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.9555G>C (p.Lys3185Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 152762 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Congenital Multicore Myopathy With External Ophthalmoplegia, allowing no conclusion about variant significance. c.9555G>C has been reported in the literature in at least one individual affected with a neurodevelopmental disorder (Sanchis-Juan_2023). 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: 37541188). ClinVar contains an entry for this variant (Variation ID: 649704). Based on the evidence outlined above, the variant was classified as uncertain significance.