rs1553688970

Variant names:

• chr3-11022384-CCGCTGGCCACTGGCCATCA-C
• rs1553688970
• NM_003042.4:c.640_658delCTGGCCATCACGCTGGCCA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003042.4(SLC6A1):​c.640_658delCTGGCCATCACGCTGGCCA​(p.Leu214SerfsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC6A1 NM_003042.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.77
• Publications: 0 publications found

Genes affected

SLC6A1 (HGNC:11042): (solute carrier family 6 member 1) The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

SLC6A1 Gene-Disease associations (from GenCC):

• epilepsy with myoclonic atonic seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-11022384-CCGCTGGCCACTGGCCATCA-C is Pathogenic according to our data. Variant chr3-11022384-CCGCTGGCCACTGGCCATCA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 475488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003042.4. 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
	SLC6A1	NM_003042.4	MANE Select	c.640_658delCTGGCCATCACGCTGGCCA	p.Leu214SerfsTer32	frameshift	Exon 7 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.640_658delCTGGCCATCACGCTGGCCA	p.Leu214SerfsTer32	frameshift	Exon 7 of 16	NP_001335179.1
	SLC6A1	NM_001348251.2		c.280_298delCTGGCCATCACGCTGGCCA	p.Leu94SerfsTer32	frameshift	Exon 7 of 16	NP_001335180.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	ENST00000287766.10	TSL:1 MANE Select	c.640_658delCTGGCCATCACGCTGGCCA	p.Leu214SerfsTer32	frameshift	Exon 7 of 16	ENSP00000287766.4
	SLC6A1	ENST00000698198.1		c.712_730delCTGGCCATCACGCTGGCCA	p.Leu238SerfsTer32	frameshift	Exon 5 of 14	ENSP00000513602.1
	SLC6A1	ENST00000644803.1		c.640_658delCTGGCCATCACGCTGGCCA	p.Leu214SerfsTer32	frameshift	Exon 5 of 14	ENSP00000494469.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Epilepsy with myoclonic atonic seizures (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
-	-	-	SLC6A1-related neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.8
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553688970; hg19: chr3-11064070;