rs1553688970

Positions:

• chr3-11022384-CCGCTGGCCACTGGCCATCA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000287766.10(SLC6A1):​c.640_658del​(p.Leu214SerfsTer32) variant causes a frameshift 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC6A1 ENST00000287766.10 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.77

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 3-11022384-CCGCTGGCCACTGGCCATCA-C is Pathogenic according to our data. Variant chr3-11022384-CCGCTGGCCACTGGCCATCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 475488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.640_658del	p.Leu214SerfsTer32	frameshift_variant	7/16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.640_658del	p.Leu214SerfsTer32	frameshift_variant	7/16	1	NM_003042.4	ENSP00000287766	P1

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

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2018

The c.640_658del19 pathogenic mutation, located in coding exon 5 of the SLC6A1 gene, results from a deletion of 19 nucleotides at nucleotide positions 640 to 658, causing a translational frameshift with a predicted alternate stop codon (p.L214Sfs*32). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Myoclonic-atonic epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change creates a premature translational stop signal (p.Leu214Serfs*32) in the SLC6A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A1 are known to be pathogenic (PMID: 25865495). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC6A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 475488). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 13, 2024

Identified in the heterozygous state in two individuals from a cohort of patients clinically diagnosed with various forms of epilepsy, but familial segregation information and additional clinical information were not included (PMID: 31440721); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37647852, 35982159, 35982160, 31440721) -

Myoclonic-astatic epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

SLC6A1-related neurodevelopmental disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

Variant interpreted as Likely pathogenic and reported on 03-22-2021 by Lab or GTR ID Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

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: rs1553688970; hg19: chr3-11064070;