11-20626741-G-TT

Position:

• chr11-20626741-G-TT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004211.5(SLC6A5):​c.1294delGinsTT​(p.Val432fs) 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 (★). 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

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 5762.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.1294delGinsTT	p.Val432fs	frameshift_variant, missense_variant	8/16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.592delGinsTT	p.Val198fs	frameshift_variant, missense_variant	7/15		NP_001305298.1
SLC6A5	XM_017018544.3	c.418delGinsTT	p.Val140fs	frameshift_variant, missense_variant	4/12		XP_016874033.1
SLC6A5	XR_007062528.1	n.672delGinsTT		non_coding_transcript_exon_variant	5/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.1294delGinsTT	p.Val432fs	frameshift_variant, missense_variant	8/16	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.*591delGinsTT		non_coding_transcript_exon_variant	7/15	1		ENSP00000298923.7
SLC6A5	ENST00000298923.11	n.*591delGinsTT		3_prime_UTR_variant	7/15	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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2022	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SLC6A5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). 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). -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 04, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -

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: rs281864924; hg19: chr11-20648287;