3-15635636-T-G

Variant names:

• chr3-15635636-T-G
• rs587783002
• NM_001370658.1:c.197T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001370658.1(BTD):​c.197T>G​(p.Met66Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,088 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M66V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.99
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.942
• PP5: Variant 3-15635636-T-G is Pathogenic according to our data. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.197T>G	p.Met66Arg	missense_variant	Exon 2 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.197T>G	p.Met66Arg	missense_variant	Exon 2 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251402 AF XY: 0.00000736

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727248

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Pathogenic:3

Jul 03, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Molecular Genetics Diagnostic Laboratory, Detroit Medical Center University Laboratories

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the BTD protein (p.Met86Arg). This variant is present in population databases (rs587783002, gnomAD 0.0009%). This missense change has been observed in individual(s) with partial biotinidase deficiency (PMID: 24797656, 25144890, 26361991). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 156000). 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. -

not specified Uncertain:1

Jul 18, 2023

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.197T>G (p.Met66Arg) 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 4e-06 in 251402 control chromosomes (gnomAD). c.197T>G has been reported in the literature in individuals affected with Partial Biotinidase Deficiency (examples: Li_2014, Jay_2015 and Gannavarapu_2015). These data indicate that the variant may be associated with disease. 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: 26361991, 25144890, 24797656). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	.;.;D;.;.;.;.;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;D;D;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	.;.;M;.;.;.;.;.;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.5	.;D;.;.;.;.;D;D;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;.;.;.;.;D;D;D;.
Sift4G	Pathogenic	0.0010	.;D;.;.;.;.;D;D;D;.
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.
Vest4		0.92, 0.91, 0.92
MutPred		0.77		.;.;Gain of disorder (P = 0.0857);.;Gain of disorder (P = 0.0857);.;.;.;.;.;
MVP		0.99
MPC		0.49
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.0062	Neutral
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	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: rs587783002; hg19: chr3-15677143;