rs80338898

Positions:

• chr15-80173089-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000137.4(FAH):​c.782C>T​(p.Pro261Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,614,094 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 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: FAH NM_000137.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 7.22

Genes affected

FAH (HGNC:3579): (fumarylacetoacetate hydrolase) Predicted to enable fumarylacetoacetase activity. Predicted to be involved in L-phenylalanine catabolic process; homogentisate catabolic process; and tyrosine catabolic process. Predicted to act upstream of or within arginine catabolic process. Located in extracellular exosome. Implicated in tyrosinemia type I. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 15-80173089-C-T is Pathogenic according to our data. Variant chr15-80173089-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAH	NM_000137.4	c.782C>T	p.Pro261Leu	missense_variant	9/14	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.782C>T	p.Pro261Leu	missense_variant	10/15		NP_001361306.1
FAH	NM_001374380.1	c.782C>T	p.Pro261Leu	missense_variant	10/15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.782C>T	p.Pro261Leu	missense_variant	9/14	1	NM_000137.4	ENSP00000453347	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251484 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.000116 AC XY: 84 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000369 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Pathogenic:8 Other:1

Pathogenic, flagged submission	clinical testing	Illumina Laboratory Services, Illumina	Sep 13, 2017	The FAH c.782C>T (p.Pro261Leu) variant is one of the four most common variants seen in patients with tyrosinemia type I, and is often observed in affected individuals of Ashkenazi Jewish descent (Sniderman King et al. 2017). The p.Pro261Leu variant has been reported in three studies in which it is found in a homozygous state in seven Israeli individuals with tyrosinemia type I (Bergman et al. 1998; Elpeleg et al. 2002; Korman and Gutman 2004). Control data are unavailable for this variant, which is reported at a frequency of 0.00374 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Pro261Leu variant is classified as pathogenic for tyrosinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2016	Variant summary: The FAH c.782C>T (p.Pro261Leu) variant located in the fumarylacetoacestase, C-terminal-related domain (via InterPro) causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with allele frequency of 16/121404, predominantly in the European (Non-Finnish), 15/66732 (1/4448), which does not exceed the estimated maximal expected allele frequency for a pathogenic FAH variant of 1/400. The variant of interest has been reported in multiple affected individuals in a homozygous state via publications. In addition, multiple reputable databases/clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 261 of the FAH protein (p.Pro261Leu). This variant is present in population databases (rs80338898, gnomAD 0.4%). This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 9633815, 11754109, 21764616, 31998365, 35800472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21058). 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 FAH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000137.2(FAH):c.782C>T(P261L) is classified as likely pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 11754109, 9633815, 15187789, and 9633815. Classification of NM_000137.2(FAH):c.782C>T(P261L) is based on the following criteria: This variant 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.‚Äã -
not provided, no classification provided	literature only	GeneReviews	-	Ashkenazi Jewish-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015]. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 16, 2022	The FAH c.782C>T (p.Pro261Leu) missense variant results in the substitution of proline at amino acid position 261 with leucine and is one of the common pathogenic variant in this gene (PMID: 20301688). Across a selection of the available literature, this variant has been identified in at least eleven individuals with tyrosinemia type 1, all in a homozygous state (PMID: 9633815; PMID: 11754109; PMID: 21764616). The highest frequency of this allele in the Genome Aggregation Database is 0.003664 in the Ashkenazi Jewish population (version 2.1.1). The variant accounts for more than 99% of the pathogenic variants in this population (PMID: 20301688). Site-directed mutagenesis, enzymatic assays, and molecular dynamics simulations with the variant protein revealed that the p.Pro261Leu variant protein results in destabilized protein with <10% of enzymatic activity compared to wild-type FAH (PMID: 31300554). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.782C>T (p.Pro261Leu) variant is classified as pathogenic for tyrosinemia type 1. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	Functional studies found that this variant is associated with approximately 8% residual enzyme activity compared to wild-type and results in destabilization of the enzyme (Macias et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25681080, 9633815, 11754109, 25087612, 27415407, 22975760, 21764616, 30414057, 31300554, 29625052, 31130284, 31998365, 31980526, 15187789, 31589614) -

FAH-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2024

The FAH c.782C>T variant is predicted to result in the amino acid substitution p.Pro261Leu. This variant has previously been reported to be causative for autosomal recessive tyrosinemia type 1. It is one of the most common pathogenic variants in this gene, and functional studies support its pathogenicity (Bergman et al. 1998. PubMed ID: 9633815; Elpeleg et al. 2002. PubMed ID: 11754109; Angileri et al. 2015. PubMed ID: 25681080; Macias et al. 2019. PubMed ID: 31300554; OMIM #276700). This variant is reported in 0.37% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.7	H;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-9.4	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MVP		0.98
MPC		0.85
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
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: rs80338898; hg19: chr15-80465431; COSMIC: COSV105066225; COSMIC: COSV105066225;