3-15641932-G-C

Variant names:

• chr3-15641932-G-C
• rs397514352
• NM_001370658.1:c.274G>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001370658.1(BTD):​c.274G>C​(p.Glu92Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,016 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E92K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0
• Publications: 2 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 19 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, 6 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-15641932-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2734449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.987
• PP5: Variant 3-15641932-G-C is Pathogenic according to our data. Variant chr3-15641932-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 24997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.274G>C	p.Glu92Gln	missense	Exon 3 of 4	NP_001357587.1
	BTD	NM_001281723.4		c.274G>C	p.Glu92Gln	missense	Exon 3 of 4	NP_001268652.2
	BTD	NM_001281724.3		c.274G>C	p.Glu92Gln	missense	Exon 5 of 6	NP_001268653.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	ENST00000643237.3	MANE Select	c.274G>C	p.Glu92Gln	missense	Exon 3 of 4	ENSP00000495254.2
	BTD	ENST00000303498.10	TSL:1	c.274G>C	p.Glu92Gln	missense	Exon 4 of 5	ENSP00000306477.6
	BTD	ENST00000427382.2	TSL:4	c.274G>C	p.Glu92Gln	missense	Exon 3 of 4	ENSP00000397113.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461016 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726746

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111456

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:2

Sep 25, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BTD c.274G>C (p.Glu92Gln) results in a conservative amino acid change located in the carbon-nitrogen hydrolase domain of the encoded protein sequence. This amino acid position has also been reported to be part of the catalytic triad active site (e.g.,Pindolia_2010 ). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250318 control chromosomes. c.274G>C has been reported in the literature in two compound heterozygous siblings affected with Biotinidase Deficiency (e.g, Pomponio_1997, Norrgard_1999). These data indicate that the variant may be associated with disease. Additionally, serum from a patient compound heterozygous with a null variant, showed that this variant resulted in protein with no detectable hydrolase or transferase activity (e.g, Pomponio_1997). The following publications have been ascertained in the context of this evaluation (PMID: 10400129, 20556795, 9396567). ClinVar contains an entry for this variant (Variation ID: 24997). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Jul 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with profound biotinidase deficiency (PMID: 9396567). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 24997). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. The observation of one or more missense substitutions at this codon (p.Glu112Gln, p.Glu112Lys) in affected individuals suggests that this may be a clinically significant residue (PMID: 9396567, 14707518). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 112 of the BTD protein (p.Glu112Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine.

not provided Pathogenic:1

May 25, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		10
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.95		Loss of sheet (P = 0.3635)
MVP		0.99
MPC		0.42
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.99
Mutation Taster		=4/96	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: rs397514352; hg19: chr3-15683439;