rs281864924

Variant names:

• chr11-20626741-G-TT
• rs281864924
• NM_004211.5:c.1294delGinsTT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004211.5(SLC6A5):​c.1294delGinsTT​(p.Val432PhefsTer99) variant causes a frameshift, missense 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V432I) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A5 NM_004211.5 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.19
• Publications: 2 publications found

Genes affected

SLC6A5 (HGNC:11051): (solute carrier family 6 member 5) This gene encodes a sodium- and chloride-dependent glycine neurotransmitter transporter. This integral membrane glycoprotein is responsible for the clearance of extracellular glycine during glycine-mediated neurotransmission. This protein is found in glycinergic axons and maintains a high presynaptic pool of neurotransmitter at glycinergic synapses. Mutations in this gene cause hyperekplexia; a heterogenous neurological disorder characterized by exaggerated startle responses and neonatal apnea. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

SLC6A5 Gene-Disease associations (from GenCC):

• hyperekplexia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 11-20626741-G-TT is Pathogenic according to our data. Variant chr11-20626741-G-TT is described in ClinVar as Pathogenic. ClinVar VariationId is 5762.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.1294delGinsTT	p.Val432PhefsTer99	frameshift_variant, missense_variant	Exon 8 of 16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.592delGinsTT	p.Val198PhefsTer99	frameshift_variant, missense_variant	Exon 7 of 15		NP_001305298.1
SLC6A5	XM_017018544.3	c.418delGinsTT	p.Val140PhefsTer99	frameshift_variant, missense_variant	Exon 4 of 12		XP_016874033.1
SLC6A5	XR_007062528.1	n.672delGinsTT		non_coding_transcript_exon_variant	Exon 5 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.1294delGinsTT	p.Val432PhefsTer99	frameshift_variant, missense_variant	Exon 8 of 16	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.*591delGinsTT		non_coding_transcript_exon_variant	Exon 7 of 15	1		ENSP00000298923.7
SLC6A5	ENST00000298923.11	n.*591delGinsTT		3_prime_UTR_variant	Exon 7 of 15	1		ENSP00000298923.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 3 Pathogenic:3

Oct 04, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jan 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val432Phefs*99) in the SLC6A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A5 are known to be pathogenic (PMID: 14622583, 16751771, 22700964). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SLC6A5-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.2
Mutation Taster		=21/179	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs281864924; hg19: chr11-20648287;