NM_018122.5:c.228-21_228-20delTTinsC

Variant names:

• chr1-173828312-TT-C
• rs1553201258
• NM_018122.5:c.228-21_228-20delTTinsC

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_018122.5(DARS2):​c.228-21_228-20delTTinsC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005907405: "In vitro functional studies provide some evidence that the c.228-21_228-20delTTinsC variant may impact protein function." PMID:24566671" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 27)
• Consequence: DARS2 NM_018122.5 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.51
• Publications: 2 publications found

Genes affected

DARS2 (HGNC:25538): (aspartyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). [provided by RefSeq, Nov 2009]

DARS2 Gene-Disease associations (from GenCC):

• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005907405: "In vitro functional studies provide some evidence that the c.228-21_228-20delTTinsC variant may impact protein function." PMID:24566671; SCV004039679: RNA studies demonstrate a damaging effect: skipping of exon 3 particularly in neuronal cells (PMID: 22023289); SCV005833942: Studies have shown that this variant alters DARS2 gene expression (PMID: 22023289).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-173828312-TT-C is Pathogenic according to our data. Variant chr1-173828312-TT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018122.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	NM_018122.5	MANE Select	c.228-21_228-20delTTinsC		intron	N/A	NP_060592.2
	DARS2	NM_001365212.1		c.228-21_228-20delTTinsC		intron	N/A	NP_001352141.1	A0A3B3IT01
	DARS2	NM_001365213.2		c.228-21_228-20delTTinsC		intron	N/A	NP_001352142.1	A0A3B3ITS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	ENST00000649689.2	MANE Select	c.228-21_228-20delTTinsC		intron	N/A	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.228-21_228-20delTTinsC		intron	N/A	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.228-21_228-20delTTinsC		intron	N/A	ENSP00000563415.1

Frequencies

GnomAD3 genomes Cov.: 27

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

GnomAD4 genome Cov.: 27

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (4)
2	-	-	not provided (2)
1	-	-	Clubfoot;C0018099:Gout;C0020538:Hypertensive disorder;C0311394:Difficulty walking;C0338474:CNS demyelination;C1112256:Sensorimotor neuropathy;C1849134:Impaired vibration sensation in the lower limbs;C4025609:EMG: axonal abnormality;C4551583:Cerebral cortical atrophy;C5399834:Abnormal foot morphology (1)
1	-	-	Dysmetria;C0751837:Gait ataxia;C1836150:Gait imbalance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=40/60	disease causing

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1553201258; hg19: chr1-173797450;