rs1554261668

Variant names:

• chr6-52479696-GAGAGCAACGC-TTTTGAAATACA
• rs1554261668
• NM_018100.4:c.1549_1559delGAGAGCAACGCinsTTTTGAAATACA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_018100.4(EFHC1):​c.1549_1559delGAGAGCAACGCinsTTTTGAAATACA​(p.Glu517PhefsTer2) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFHC1 NM_018100.4 frameshift, stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

Genes affected

EFHC1 (HGNC:16406): (EF-hand domain containing 1) This gene encodes an EF-hand-containing calcium binding protein. The encoded protein likely plays a role in calcium homeostasis. Mutations in this gene have been associated with susceptibility to juvenile myoclonic epilepsy and juvenile absence epilepsy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

EFHC1 Gene-Disease associations (from GenCC):

• juvenile myoclonic epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC1	NM_018100.4	c.1549_1559delGAGAGCAACGCinsTTTTGAAATACA	p.Glu517PhefsTer2	frameshift_variant, stop_gained	Exon 9 of 11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2	c.1492_1502delGAGAGCAACGCinsTTTTGAAATACA	p.Glu498PhefsTer2	frameshift_variant, stop_gained	Exon 10 of 12		NP_001165891.1
EFHC1	NR_033327.2	n.2875_2885delGAGAGCAACGCinsTTTTGAAATACA		non_coding_transcript_exon_variant	Exon 8 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11	c.1549_1559delGAGAGCAACGCinsTTTTGAAATACA	p.Glu517PhefsTer2	frameshift_variant, stop_gained	Exon 9 of 11	1	NM_018100.4	ENSP00000360107.4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoclonic epilepsy, juvenile, susceptibility to, 1;C5551411:Typical absence seizure Uncertain:1

Mar 20, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu517Phefs*2) in the EFHC1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EFHC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 534105). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in EFHC1 cause disease. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

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

Other links and lift over

dbSNP: rs1554261668; hg19: chr6-52344494;