rs80338685

chr3-15645224-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001370658.1(BTD):c.1308A>C(p.Gln436His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 B:1 O:1
• Conservation: PhyloP100: 1.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15645224-A-C is Pathogenic according to our data. Variant chr3-15645224-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645224-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.1308A>C	p.Gln436His	missense_variant	4/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.1308A>C	p.Gln436His	missense_variant	4/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000414 AC: 104 AN: 251420 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135878

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000699 AC: 1022 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.000664 AC XY: 483 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000881

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74432

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000774 Hom.: 1

Bravo AF: 0.000453

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000763

EpiControl AF: 0.000711

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Benign:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:19 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000060.2(BTD):c.1368A>C(Q456H) is classified as pathogenic in the context of biotinidase deficiency. Sources cited for classification include the following: PMID 9232193, 11313766, 22698809, 17185019, 20224900, 23644139 and 26361991. Classification of NM_000060.2(BTD):c.1368A>C(Q456H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 08, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 19, 2022	The BTD c.1308A>C; p.Gln436His variant (rs80338685, c.1368A>C; p.Gln456His on NM_000060.3) is reported to be the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States (Norrgard 1997). This variant is reported in ClinVar (Variation ID: 1902). It is found in the general population with an overall allele frequency of 0.04% (115/282806 alleles) in the Genome Aggregation Database. The glutamine at codon 456 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, the variant enzyme in the homozygous state has very low biotinyl-hydrolase activity and lacks biotinyl-transferase activity (Norrgard 1997). Based on available information, this variant is considered to be severely pathogenic. References: Norrgard KJ et al. Mutation (Q456H) is the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Biochem Mol Med. 1997 Jun;61(1):22-7. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 456 of the BTD protein (p.Gln456His). This variant is present in population databases (rs80338685, gnomAD 0.08%). This missense change has been observed in individual(s) with BTD-related conditions (PMID: 10400129, 10801053, 11313766, 24797656, 25423671, 26810761, 27329734). ClinVar contains an entry for this variant (Variation ID: 1902). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2000	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 03, 2022	ACMG classification criteria: PM2, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 24, 2022	The p.(Gln456His) variant is a well-established pathogenic variant (PMID: 20301497), reported in multiple individuals and classified as pathogenic by multiple laboratories (ClinVar). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 30, 2017	The BTD c.1368A>C (p.Gln456His) missense variant is described as one of the most common variants in individuals with biotinidase deficiency (Norrgard et al. 1997). The p.Gln456His variant has been reported in at least 16 individuals with partial or profound biotinidase deficiency including two in a homozygous state and 14 in a compound heterozygous state (Norrgard et al. 1997; Thodi et al. 2013; Wolf 2017; Borsatto et al. 2017). The p.Gln456His variant was absent from 632 controls (Norrgard et al. 1997) but is reported at a frequency of 0.00151 in the European American population of the Exome Sequencing Project. Serum from a homozygous individual showed reduced cross reacting material to a polyclonal antibody compared with serum from normal controls, and decreased or no activity of biotinyl-hydrolase and biotinyl-transferase was also observed (Norrgard et al. 1997). Based on the evidence, the p.Gln456His variant is classified as pathogenic for biotinidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2023	Variant summary: BTD c.1308A>C (p.Gln436His) results in a non-conservative amino acid change in 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 0.00041 in 251420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BTD causing Biotinidase Deficiency (0.00041 vs 0.0046), allowing no conclusion about variant significance. c.1308A>C has been reported in the literature in multiple individuals affected with Biotinidase Deficiency (e.g. Norrgard_1997, Wolf_2017). These data indicate that the variant is very likely to be associated with disease. Multiple publications report that biotinase activity in patients carrying this variant or in mutant plasmid has <20% of normal activity (e.g. Norrgard_1997, Wolf_2017, Liu_2018). 19 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with 18 submitters classifying the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 22, 2021	This BTD variant (rs80338685) is rare (<0.1%) in a large population dataset (gnomAD: 115/282806 total alleles, 0.04%, no homozygotes) and has an entry in ClinVar. It is a common cause of profound bioitinidase deficiency (less than 10% mean normal activity in serum) when it occurs in a homozygous or compound heterozygous state with another pathogenic BTD variant and is the most common BTD variant identified in children with profound biotinidase deficiency by newborn screening in the United States. This variant has been reported in a compound heterozygous state (in trans) with the complex allele c.[451G>A;1207G>C] in multiple unrelated individuals with profound biotinidase deficiency. We consider c.1308A>C to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 07, 2015	This patient is a carrier of a heterozygous pathogenic variant in the BTD gene associated with autosomal recessive biotinidase deficiency (MIM 253260). This BTD variant (c.1374A>C) was identified in several patients in both the homozygous and compound heterozygous state, and is one of the most common pathogenic mutations identified in this gene through newborn screening programs in populations of northern European ancestry (Norrgard et al. 1997, PMID 9232193; Wolf et al. 1997, PMID: 9375914; Norrgard et al. 1999, PMID: 10400129; Pomponio et al. 2000, PMID: 10801053). Biochemical analyses of patients with this mutation have supported the role this mutation plays in causing biotinidase deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Feb 08, 2022	ACMG categories: PS3,PM3,PM7,PP3,PP5,BP1 -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 30, 2020	This variant is the most common pathogenic variant associated with profound biotinidase deficiency (PMID: 9232193 (1997)). Individuals who are compound heterozygous for this variant and other pathogenic BTD variants, or homozygous for this variant, have been reported to be affected with partial or profound biotinidase deficiency in the published literature (PMIDs: 9232193 (1997), 9654207 (1998), 10801053 (2000), 11668630 (2001), 17185019 (2007), 22698809 (2012), 23644139 (2013), 26361991 (2015), 27329734 (2016), 27657684 (2017), and 28971021 (2017)). In addition, a functional analysis on the effect of this variant reports decreased biotinidase activity in vitro (PMID: 29359854 (2018)). Therefore, the variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2020	Functional analysis found Q456H is associated with significantly reduced enzyme activity compared to wild-type (Liu et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26810761, 27329734, 11313766, 9375914, 22975760, 25087612, 9232193, 27657684, 28971021, 9654207, 23644139, 24797656, 10400129, 10801053, 25423671, 29359854, 31980526) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BTD: PM3:Very Strong, PM2, PS3:Supporting -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.1368A>C (p.Q456H) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a A to C substitution at nucleotide position 1368, causing the glutamine (Q) at amino acid position 456 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the BTD c.1368A>C alteration was observed in 0.04% (115/282806) of total alleles studied, with a frequency of 0.08% (100/129138) in the European (non-Finnish) subpopulation. This mutation has been identified in the homozygous and compound heterozygous states in multiple unrelated patients with biotinidase deficiency (Norrgard, 1999; Pomponio, 2000; Funghini, 2020). The Q456H mutation is the most common BTD mutation ascertained by newborn screening in the United States, having been identified on 28% of alleles of children with profound biotinidase deficiency (Norrgard, 1997). Serum from a patient who was homozygous for the Q456H mutation had greatly reduced quantities of cross-reacting material to anti-biotinidase antibody, profoundly deficient biotinyl-hydrolase activity, and no biotinyl-transferase activity (Norrgard, 1997). The p.Q456H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.55	T
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.97, 0.98, 0.96
MutPred		0.94		.;.;Gain of sheet (P = 0.0477);.;.;.;.;
MVP		0.96
MPC		0.41
ClinPred		0.22	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
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

Other links and lift over

dbSNP: rs80338685; hg19: chr3-15686731;