chr5-1212338-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting

The NM_001003841.3(SLC6A19):c.517G>A(p.Asp173Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0031 in 1,613,638 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 12 hom. )

Consequence

SLC6A19
NM_001003841.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17U:1

Conservation

PhyloP100: 4.03

Variant links:

Genes affected

SLC6A19 (HGNC:27960): (solute carrier family 6 member 19) This gene encodes a system B(0) transmembrane protein that actively transports most neutral amino acids across the apical membrane of epithelial cells. Mutations in this gene may result in Hartnup disorder, an inherited disease with symptoms such as pellagra, cerebellar ataxia, and psychosis. The expression and function of B0AT1 (SLC6A19) in intestinal cells depends on the presence of the accessory protein angiotensin-converting enzyme 2 (ACE2) which, among other functions, acts as a chaperone for membrane trafficking of B0AT1. The ACE2 is also the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and for SARS-CoV-2 that is causing the coronavirus 2019 (COVID-19) pandemic [provided by RefSeq, Jul 2020]

SLC6A19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PP5

Variant 5-1212338-G-A is Pathogenic according to our data. Variant chr5-1212338-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1212338-G-A is described in Lovd as [Pathogenic]. Variant chr5-1212338-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.03069511). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (250/152250) while in subpopulation NFE AF= 0.00316 (215/67992). AF 95% confidence interval is 0.00282. There are 0 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A19	NM_001003841.3 link	c.517G>A	p.Asp173Asn	missense_variant	Exon 4 of 12	ENST00000304460.11	NP_001003841.1	Q695T7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A19	ENST00000304460.11 link	c.517G>A	p.Asp173Asn	missense_variant	Exon 4 of 12	1	NM_001003841.3	ENSP00000305302.10		Q695T7
SLC6A19	ENST00000515652.5 link	n.425G>A		non_coding_transcript_exon_variant	Exon 4 of 11	2		ENSP00000425701.1		E9PD72

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

251

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00156

AC:

392

AN:

250978

Hom.:

AF XY:

0.00148

AC XY:

201

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00307

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00326

AC:

4758

AN:

1461388

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

2303

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.00411

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00164

AC:

250

AN:

152250

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00316

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00288

Hom.:

Bravo

AF:

0.00166

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00163

AC:

198

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00314

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies have shown the SLC6A19 transport activity was reduced in the D173N construct compared to wild type (PMID: 19185582, 15286788); This variant is associated with the following publications: (PMID: 28787443, 15286788, 17555458, 25082825, 29431110, 30665703, 30487145, 31908951, 31980526, 34041853, 33848968, 31589614, 34426522, 18484095, 34297361, 19185582) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 173 of the SLC6A19 protein (p.Asp173Asn). This variant is present in population databases (rs121434346, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Hartnup disorder (PMID: 15286788, 17555458, 18484095, 21814048). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2019). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC6A19 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC6A19 function (PMID: 15286788, 19185582). For these reasons, this variant has been classified as Pathogenic. -

Jul 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PM3_very_strong, PS3_supporting -

Neutral 1 amino acid transport defect

Pathogenic:6

Dec 19, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC6A19 c.517G>A (p.Asp173Asn) results in a conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 250978 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. c.517G>A has been reported in the literature in multiple individuals affected with Hartnup Disease (Seow_2004, Schuermans_2022), including those that were compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant resulted in <50% of wild type leucine transport activity (Seow_2004). The following publications have been ascertained in the context of this evaluation (PMID: 15286788, 35606766). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=10), likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp173Asn (NM_001003841.2 c.517G>A) variant in the SLC6A19 gene has been r eported at least 10 individuals with Hartnup disease, 2 of whom were homozygous and 8 of whom were compound heterozygous with another SLC6A19 variant (Seow 2004 , Azmanov 2008). This is the most frequent pathogenic variant in patients of Eur opean descent (Azmanov 2007). This variant has also been reported in ClinVar (V ariation ID#2019), as pathogenic or likely pathogenic by three laboratories. In vitro studies indicate this variant causes a partial inactivation of the protein (Seow 2004, Camargo 2009). The p.Asp173Asn variant has been identified in 0.3% (384/126,562) of European chromosomes by the Genome Aggregation Database (gnomAD ; http://gnomad.broadinstitute.org; dbSNP rs121434346), though this frequency is low enough to be consistent with a recessive carrier frequency. In summary, th is variant meets our criteria to be classified as pathogenic for Hartnup disease in an autosomal recessive manner based on functional studies and its occurrence in individuals with this disease. -

SLC6A19-related disorder

Pathogenic:1

Sep 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC6A19 c.517G>A variant is predicted to result in the amino acid substitution p.Asp173Asn. This variant has been reported in individuals with autosomal recessive Hartnup disorder and results in reduced transport activity compared to wild type (Seow et al. 2004. PubMed ID: 15286788; Camargo et al. 2009. PubMed ID: 19185582). This variant is reported in 0.30% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Neutral 1 amino acid transport defect;C0268654:Iminoglycinuria;C0543541:Hyperglycinuria

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

Eigen

Benign

-0.13

Eigen_PC

Benign

0.059

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.043

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.020

REVEL

Benign

0.18

Sift

Benign

0.45

Sift4G

Benign

0.62

Polyphen

0.016

Vest4

0.79

MVP

0.80

MPC

0.73

ClinPred

0.76

GERP RS

5.1

Varity_R

0.48

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over