rs397507176

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PP2PP5BP4BS1_SupportingBS2_Supporting

The NM_001370658.1(BTD):c.908A>G(p.His303Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000952 in 1,614,216 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 24 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:8

Conservation

PhyloP100: 7.25

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

biotinidase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

BTD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 88 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -0.52516 (below the threshold of 3.09). Trascript score misZ: 0.15371 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, biotinidase deficiency.

PP5

Variant 3-15644824-A-G is Pathogenic according to our data. Variant chr3-15644824-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38278.

BP4

Computational evidence support a benign effect (MetaRNN=0.013572812). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.001 (1463/1461888) while in subpopulation SAS AF = 0.016 (1379/86258). AF 95% confidence interval is 0.0153. There are 24 homozygotes in GnomAdExome4. There are 1024 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 24 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1 link	c.908A>G	p.His303Arg	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.908A>G	p.His303Arg	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00205

AC:

516

AN:

251360

AF XY:

0.00280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00100

AC:

1463

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

1024

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0160

AC:

1379

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1112012

Other (OTH)

AF:

0.00103

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

126

252

377

503

629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000486

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.0147

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.00231

AC:

281

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:4Uncertain:5

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 25, 2017

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 31, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 27, 2024

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 05, 2024

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 323 of the BTD protein (p.His323Arg). This variant is present in population databases (rs397507176, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with partial BTD deficiency who showed 10-30% of normal BTD enzymatic activity (PMID: 9654207, 26361991). ClinVar contains an entry for this variant (Variation ID: 38278). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTD protein function. Experimental studies have shown that this missense change affects BTD function (PMID: 9654207, 24797656). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Aug 08, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple individuals with a second reported BTD variant (phasing unclear), who were affected with partial biotinidase deficiency (10-30% of normal BTD enzymatic activity) (PMIDs: 35195902, 9654207, 26361991, 32300527, 38141137, 27329734). This variant has also been reported as likely pathogenic/pathogenic and as a VUS by clinical laboratories in ClinVar. Additional information: Variant is predicted to result in a missense amino acid change from histidine to arginine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Variant is present in gnomAD (v4) >=0.01 and <0.03 for a recessive condition (1489 heterozygotes, 24 homozygotes); No comparable missense variants have previous evidence for pathogenicity; Variant is located in the annotated biotinidase_like domain (NCBI); Missense variant with conflicting in silico predictions and high conservation; Loss of function is a known mechanism of disease in this gene and is associated with biotinidase deficiency (MIM#253260); Variants in this gene are known to have variable expressivity. The condition associated with this gene is known to range from partial, with milder symptoms and later onset, to profound, with more severe symptoms and earlier onset. Also, individuals with the same genotype have been observed to have different clinical and biochemical phenotypes (PMIDs: 20301497, 28498829); This variant has been shown to be paternally inherited by trio analysis.

Nov 04, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Pathogenic:2Uncertain:2

Nov 15, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant has been described in two heterozygous cases with a severe genotype (PMID: 33217065 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Taking into account the available information, we are unable to determine the clinical significance of this variant.

Nov 06, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The phenotype of individuals homozygous for p.(H303R) is unclear, as it is observed in apparent homozygous state in multiple unrelated individuals in large population cohorts (gnomAD) and healthy adult individuals tested at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.968A>G; p.(H323R); This variant is associated with the following publications: (PMID: 31191208, 24066991, 27535533, 28498829, 27657684, 27014582, 26810761, 22698809, 9654207, 26361991, 11668630, 32300527, 36684547, 35195902, 27329734, 17382128, 24797656)

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BTD: PM2, PM3, PP4:Moderate

Dec 10, 2012

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Sep 21, 2021

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.968A>G (p.H323R) alteration is located in coding exon 4 of the BTD gene. This alteration results from an A to G substitution at nucleotide position 968, causing the histidine (H) at amino acid position 323 to be replaced by an arginine (R). The BTD c.968A>G alteration has been reported previously in the compound heterozygous state in multiple individuals with enzyme levels consistent with partial biotinidase deficiency (Swango, 1998; Li, 2014, Gannavarapu, 2015; Wiltink, 2016; Mardhiah, 2020). The c.968A>G (p.H323R) alteration is considered a hypomorphic allele and only causes disease when in trans with a more severe allele (Lek, 2015). Based on the available evidence, this alteration is classified as likely pathogenic.

not specified

Uncertain:1

Jun 17, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BTD c.908A>G (p.His303Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.0021 in 251360 control chromosomes, predominantly at a frequency of 0.017 within the South Asian subpopulation in the gnomAD database, including 8 homozygotes. c.908A>G has been observed in individual(s) affected with Biotinidase Deficiency (e.g. Swango_1998, Al-Jasmi_2016, Mardhiah_2020, Karaoglan_2020, Forny_2022, Sharma_2024, Yilmaz_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Biotinidase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26589311, 9654207, 33217065, 32300527, 35195902, 38141137, 38299772). ClinVar contains an entry for this variant (Variation ID: 38278). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

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

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.0

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

MetaRNN

Benign

0.014

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

0.0

.;.;L;.;.;.;.

PhyloP100

7.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D;.;T;.;D;D

Sift4G

Pathogenic

0.0

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

Vest4

0.0

ClinPred

0.11

GERP RS

5.8

Varity_R

0.67

gMVP

0.94

Mutation Taster

=57/43

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over