rs104893688

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001370658.1(BTD):c.1535C>T(p.Thr512Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,611,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 7.34

Variant links:

Genes affected

BTD (HGNC:1122): (biotinidase) The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]

BTD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

PP5

Variant 3-15645451-C-T is Pathogenic according to our data. Variant chr3-15645451-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645451-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1 link	c.1535C>T	p.Thr512Met	missense_variant	Exon 4 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3 link	c.1535C>T	p.Thr512Met	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2		P43251-4

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000693

AC:

AN:

245398

Hom.:

AF XY:

0.0000825

AC XY:

AN XY:

133376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

171

AN:

1459576

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

726104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000782

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000907

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000495

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:13

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM3 (very strong),PM2,PP3,PM1,PP4 -

Apr 20, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BTD c.1535C>T (p.Thr512Met, also known as c.1595C>T/p.Thr532Met in NM_000060) results in a non-conservative amino acid change located in the Vanin, C-terminal domain (IPR043957) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 245398 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (6.9e-05 vs 0.0046), allowing no conclusion about variant significance. This variant has been reported in the literature in multiple individuals (both homozygous and compound heterozygous state) affected with partial to profound Biotinidase Deficiency (example: Pomponio_2000, Lara_2015). These data indicate that the variant is very likely to be associated with disease. Less than 10% of mean normal enzymatic activity was seen in serum or plasma of patients who were homozygous for the variant of interest (Pomponio_2000). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 29, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 532 of the BTD protein (p.Thr532Met). This variant is present in population databases (rs104893688, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9654207, 10400129, 10801053, 21752405, 22011816, 22698809, 27657684). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Mediterranean ancestry (PMID: 9654207, 10400129, 10801053, 21752405, 22011816, 22698809, 27657684). ClinVar contains an entry for this variant (Variation ID: 1897). 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 expected to disrupt BTD protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PM3,PP3. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BTD c.1595C>T; p.Thr532Met variant (rs104893688), is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with partial to profound biotinidase deficiency (Cowan 2012, Funghini 2002, Laszlo 2003, Norrgard 1999, Ohlsson 2010, Pomponio 2000, Swango 1998, Wiltink 2016, Wolf 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 1897), and is found in the non-Finnish European population with an allele frequency of 0.015% (19/125,971 alleles) in the Genome Aggregation Database. The threonine at codon 532 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Thr532Met variant is considered to be severely pathogenic. References: Cowan TM et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012 Aug;106(4):485-7. Funghini S et al. Two new mutations in children affected by partial biotinidase deficiency ascertained by newborn screening. J Inherit Metab Dis. 2002 Aug;25(4):328-30. Laszlo A et al. Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies. J Inherit Metab Dis. 2003;26(7):693-8. Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. Ohlsson A et al. Profound biotinidase deficiency: a rare disease among native Swedes. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S175-8. Pomponio RJ et al. Novel mutations cause biotinidase deficiency in Turkish children. J Inherit Metab Dis. 2000 Mar;23(2):120-8. Swango KL et al. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet. 1998 May;102(5):571-5. Wiltink RC et al. Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations. Eur J Hum Genet. 2016 Oct;24(10):1424-9. Wolf B. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med. 2017 Apr;19(4):396-402. -

Jun 17, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:6

Aug 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as p.(T532M); This variant is associated with the following publications: (PMID: 26361991, 26810761, 27657684, 26589311, 25754625, 14707518, 25174816, 12227467, 22698809, 9654207, 10801053, 30912303, 34426522, 35805799, 10400129) -

Aug 10, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant found in at least one symptomatic patient. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have phenotype known to be consistent with disease. The variant predicted to have a damaging effect on the protein. -

Aug 21, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BTD: PM3:Very Strong, PM2, PS3:Supporting -

BTD-related disorder

Pathogenic:1

Aug 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BTD c.1595C>T variant is predicted to result in the amino acid substitution p.Thr532Met. This variant, also known as c.1535C>T (p.Thr512Met) in an alternate transcript (NM_001370658.1), has been reported in the homozygous and compound heterozygous state in individuals with biotinidase deficiency (Norrgard. 1999. PubMed ID: 10400129; László et al. 2003. PubMed ID: 14707518; Wolf et al. 2005. PubMed ID: 15776412; Wolf. 2017. PubMed ID: 27657684; Carvalho. 2019. PubMed ID: 30912303). This variant has been interpreted as pathogenic by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/1897/). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

May 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1595C>T (p.T532M) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a C to T substitution at nucleotide position 1595, causing the threonine (T) at amino acid position 532 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.008% (22/276796) total alleles studied. The highest observed frequency was 0.015% (19/125972) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other BTD variants in many individuals with features consistent with biotinidase deficiency; in at least one instance, the variants were identified in trans (Forny, 2022; Funghini, 2020; Wolf, 2017; Wiltink, 2016; Lara, 2015; Ohlsson, 2010; Pomponio, 2000; Norrgard, 1999; Swango, 1998). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

.;.;D;.;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

.;T;T;.;.;T;T

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.5

.;.;M;.;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.1

.;D;.;.;.;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.025

.;D;.;.;.;D;D

Sift4G

Pathogenic

0.0010

.;D;.;.;.;D;D

Polyphen

1.0

.;.;D;.;.;.;.

Vest4

0.95, 0.96, 0.95

MVP

0.93

MPC

0.43

ClinPred

0.90

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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