rs397514412

Variant names:

• chr3-15645123-T-C
• rs397514412
• NM_001370658.1:c.1207T>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001370658.1(BTD):​c.1207T>C​(p.Cys403Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,086 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 7.96
• Publications: 3 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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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, 0.991
• PP5: Variant 3-15645123-T-C is Pathogenic according to our data. Variant chr3-15645123-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 25073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1207T>C	p.Cys403Arg	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	c.1207T>C	p.Cys403Arg	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 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

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 53414

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15280

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: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

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

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:4 Uncertain:1

Nov 08, 2023

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.1207T>C (p.Cys403Arg) 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 was absent in 251372 control chromosomes. c.1207T>C, described as p.Cys423Arg, has been reported at a compound heterozygous state along with different apparently pathogenic variants in at-least four individuals affected with Biotinidase Deficiency (examples, Forny_2022, Iseghem_2019, Pomponio_1997, Wolf_2017). These data indicate that the variant is very likely to 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: 35195902, 31035122, 9396567, 27657684). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (PATH, n=1, Likely pathogenic, n=2, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 14, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

NM_000060.2(BTD):c.1267T>C(C423R) is a missense variant classified as a variant of uncertain significance in the context of biotinidase deficiency. C423R has been observed in cases with relevant disease (PMID: 10400129, 9396567, 31035122). Functional assessments of this variant are not available in the literature. C423R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000060.2(BTD):c.1267T>C(C423R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 423 of the BTD protein (p.Cys423Arg). This variant is present in population databases (rs397514412, gnomAD 0.007%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9396567, 27657684, 31035122). 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: 25073). 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. -

Jan 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 20, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and is damaging to protein function(s) relevant to disease mechanism. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	.;.;D;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;T;T;.;.;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-11	.;D;.;.;.;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0070	.;D;.;.;.;D;D
Sift4G	Pathogenic	0.0010	.;D;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.99, 1.0, 0.99
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.99
Mutation Taster		=1/99	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: rs397514412; hg19: chr3-15686630;