chr3-15645217-A-G

Variant names:

• chr3-15645217-A-G
• rs397514345
• NM_001370658.1:c.1301A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM5 PP2 PP3_Moderate PP5

The NM_001370658.1(BTD):​c.1301A>G​(p.Tyr434Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y434D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2
• Conservation: PhyloP100: 5.80
• Publications: 5 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001370658.1
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-15645216-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2151685.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 3-15645217-A-G is Pathogenic according to our data. Variant chr3-15645217-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458806.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370658.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	NM_001370658.1	MANE Select	c.1301A>G	p.Tyr434Cys	missense	Exon 4 of 4	NP_001357587.1
	BTD	NM_001281723.4		c.1301A>G	p.Tyr434Cys	missense	Exon 4 of 4	NP_001268652.2
	BTD	NM_001281724.3		c.1301A>G	p.Tyr434Cys	missense	Exon 6 of 6	NP_001268653.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	ENST00000643237.3	MANE Select	c.1301A>G	p.Tyr434Cys	missense	Exon 4 of 4	ENSP00000495254.2
	BTD	ENST00000303498.10	TSL:1	c.1301A>G	p.Tyr434Cys	missense	Exon 5 of 5	ENSP00000306477.6
	BTD	ENST00000427382.2	TSL:4	c.1301A>G	p.Tyr434Cys	missense	Exon 4 of 4	ENSP00000397113.2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000263 AC: 66 AN: 251422 AF XY: 0.000346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461876 Hom.: 1 Cov.: 31 AF XY: 0.000171 AC XY: 124 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00168 AC: 145 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111994

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74492

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000521 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000272 AC: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:6 Uncertain:2

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 454 of the BTD protein (p.Tyr454Cys). This variant is present in population databases (rs397514345, gnomAD 0.2%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761, 29995633; internal data). 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: 458806). 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.

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The observed missense c.1301A>G(p.Tyr434Cys) variant in BTD gene has been reported previously in compound heterozygous state in multiple individuals affected with biotinidase deficiency (Al-Eitan LN, et al., 2020; Muthaffar OY., 2021; Baykal T, et al., 2005). This variant has also been observed to segregate with disease in related individuals. The p.Tyr434Cys variant has been reported with allele frequency of 0.03% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely Pathogenic. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Tyr at position 434 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. Another significant variant [c.1270G>C p.Asp424His] in BTD gene was detected in the spouse (EX-2323A), id: 30607800132].

May 20, 2025

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.1301A>G (p.Tyr434Cys) 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 0.00026 in 251422 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BTD causing Biotinidase Deficiency (0.00026 vs 0.0046), allowing no conclusion about variant significance. c.1301A>G has been observed in multiple individuals affected with Biotinidase Deficiency (Ercan_2020, Canda_2018, Sharma_2023, Internal data). 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. The most pronounced variant effect results in 26%-35% of normal activity (Ercan_2020). The following publications have been ascertained in the context of this evaluation (PMID: 34448386, 33189081, 26810761, 29353266, 15776412, 29995633, 31973013, 38299772). ClinVar contains an entry for this variant (Variation ID: 458806). Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 05, 2018

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jul 26, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 16, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 10, 2024

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:2

Jul 21, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Y454C); This variant is associated with the following publications: (PMID: 30616616, 33312878, 15776412, 29995633, 26810761, 31973013, 34271776, 29353266)

May 28, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported in multiple individuals with profound or partial biotinidase deficiency (PMID: 33312878 (2020), 29995633 (2018), 26810761 (2016), 15776412 (2005)). Variant occurs in 3 or more cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and at least 3 cases have phenotype known to be consistent with disease. Variant is predicted to have a damaging effect on the protein.Based on the available information, the variant is predicted to be likely pathogenic.

BTD-related disorder Pathogenic:1

May 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BTD c.1361A>G variant is predicted to result in the amino acid substitution p.Tyr454Cys. This variant has been reported along with an additional BTD variant(s) in multiple patients with profound biotinidase deficiency (<10% enzyme activity) (Wolf et al. 2005. PubMed ID: 15776412; Procter et al. 2016. PubMed ID: 26810761; Canda et al. 2018. PubMed ID: 29995633). It has also been reported in patients with partial biotinidase deficiency (10%-30% enzyme activity) (Hsu et al. 2019. PubMed ID: 30616616; Funghini et al. 2020. PubMed ID: 33312878) and in several patients with abnormal newborn screen results suggestive of biotinidase deficiency (Seker Yilmaz et al. 2018. PubMed ID: 29353266). This variant is reported in 0.21% of alleles in individuals of South Asian descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic.

Possible mitochondrial disorder - nuclear genes Pathogenic:1

Aug 04, 2025

Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting, PP3_supporting, PM3_moderate, PP4_strong

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.89		Gain of sheet (P = 0.0221)
MVP		1.0
MPC		0.46
ClinPred		0.44	T
GERP RS		4.4
Varity_R		0.57
gMVP		0.94
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514345; hg19: chr3-15686724; COSMIC: COSV57730432; COSMIC: COSV57730432;