19-38433864-TCC-CG

Variant names:

• chr19-38433864-TCC-CG
• rs193922743
• NM_000540.3:c.35_37delTCCinsCG

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1 PS1 PM2 PP2

The NM_000540.3(RYR1):​c.35_37delTCCinsCG​(p.Phe12SerfsTer106) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RYR1 NM_000540.3 frameshift, missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.24

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 441 pathogenic variants in the truncated region.
• PS1: Transcript NM_000540.3 (RYR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RYR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 94 curated benign missense variants. Gene score misZ: 1.918 (below the threshold of 3.09). Trascript score misZ: 3.9788 (above the threshold of 3.09). GenCC associations: The gene is linked to King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.35_37delTCCinsCG	p.Phe12SerfsTer106	frameshift_variant, missense_variant	Exon 1 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.35_37delTCCinsCG	p.Phe12SerfsTer106	frameshift_variant, missense_variant	Exon 1 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.35_37delTCCinsCG	p.Phe12SerfsTer106	frameshift_variant, missense_variant	Exon 1 of 105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.35_37delTCCinsCG		non_coding_transcript_exon_variant	Exon 1 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922743; hg19: chr19-38924504;