rs121434346

Variant names:

• chr5-1212338-G-A
• rs121434346
• NM_001003841.3:c.517G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-1212338-G-A
• chr5-1212338-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS1_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. 13/23 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1
• Conservation: PhyloP100: 4.03

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check. 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	c.517G>A	p.Asp173Asn	missense_variant	Exon 4 of 12	ENST00000304460.11	NP_001003841.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152132 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.00156 AC: 392 AN: 250978 AF XY: 0.00148

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 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.: 12 Cov.: 33 AF XY: 0.00317 AC XY: 2303 AN XY: 727024

Gnomad4 AFR exome AF: 0.000597 AC: 20 AN: 33480

Gnomad4 AMR exome AF: 0.000358 AC: 16 AN: 44716

Gnomad4 ASJ exome AF: 0.000651 AC: 17 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.000267 AC: 23 AN: 86258

Gnomad4 FIN exome AF: 0.000151 AC: 8 AN: 53000

Gnomad4 NFE exome AF: 0.00411 AC: 4569 AN: 1111952

Gnomad4 Remaining exome AF: 0.00172 AC: 104 AN: 60384

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74434

Gnomad4 AFR AF: 0.000578 AC: 0.000577812 AN: 0.000577812

Gnomad4 AMR AF: 0.000196 AC: 0.000196078 AN: 0.000196078

Gnomad4 ASJ AF: 0.00115 AC: 0.00115207 AN: 0.00115207

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000621 AC: 0.000621375 AN: 0.000621375

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00316 AC: 0.00316214 AN: 0.00316214

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.00297 Hom.: 3

Bravo AF: 0.00166

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00163 AC: 198

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00314

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

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) -

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 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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. -

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

- -

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

- -

-

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

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

- -

Neutral 1 amino acid transport defect Pathogenic:7

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. -

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

- -

Aug 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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. -

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	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.18
Sift	Benign	0.45	T
Sift4G	Benign	0.62	T
Polyphen		0.016	B
Vest4		0.79
MVP		0.80
MPC		0.73
ClinPred		0.76	D
GERP RS		5.1
Varity_R		0.48
gMVP		0.72
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434346; hg19: chr5-1212453;