1-241497927-AT-ATTTT

Variant names:

• chr1-241497927-A-ATTT
• rs367543046
• NM_000143.4:c.1431_1433dupAAA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM1 PM4_Supporting PP5

The NM_000143.4(FH):​c.1431_1433dupAAA​(p.Lys477dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,964 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000283665: Experimental studies have shown that patient cells carrying this variant and another loss-of-function FH variant have significantly reduced fumarate hydratase enzyme activity (0-20%), compared to wild-type cells (PMID:9300800, 9635293, 15987702, 16151915, 24182348)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N478N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (8 hom.)
• Consequence: FH NM_000143.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21 U:8 B:1 O:1
• Conservation: PhyloP100: 1.41
• Publications: 25 publications found

Genes affected

FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]

FH Gene-Disease associations (from GenCC):

• hereditary leiomyomatosis and renal cell cancer

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Ambry Genetics
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• pheochromocytoma-paraganglioma

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• leiomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000283665: Experimental studies have shown that patient cells carrying this variant and another loss-of-function FH variant have significantly reduced fumarate hydratase enzyme activity (0-20%), compared to wild-type cells (PMID: 9300800, 9635293, 15987702, 16151915, 24182348).; SCV002070473: Functional studies have shown that the p.Lys477dup sequence change leads to significantly reduced FH enzyme activity levels (PMID: 15987702).; SCV000214800: A cell line derived from a patient with FH deficiency, who is compound heterozygous for this alteration and FH p.R233H, showed defective energy and redox metabolism at the mRNA level (Raimundo, 2008).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_000143.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000143.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-241497927-A-ATTT is Pathogenic according to our data. Variant chr1-241497927-A-ATTT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42095.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000143.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	NM_000143.4	MANE Select	c.1431_1433dupAAA	p.Lys477dup	disruptive_inframe_insertion	Exon 10 of 10	NP_000134.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	ENST00000366560.4	TSL:1 MANE Select	c.1431_1433dupAAA	p.Lys477dup	disruptive_inframe_insertion	Exon 10 of 10	ENSP00000355518.4	P07954-1
	FH	ENST00000958409.1		c.1428_1430dupAAA	p.Lys476dup	disruptive_inframe_insertion	Exon 10 of 10	ENSP00000628468.1
	FH	ENST00000932939.1		c.1383_1385dupAAA	p.Lys461dup	disruptive_inframe_insertion	Exon 10 of 10	ENSP00000602998.1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00104 AC: 259 AN: 249492 AF XY: 0.000992

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00201 AC: 2933 AN: 1461680 Hom.: 8 Cov.: 31 AF XY: 0.00197 AC XY: 1430 AN XY: 727144

African (AFR) AF: 0.000418 AC: 14 AN: 33470

American (AMR) AF: 0.000403 AC: 18 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 136 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00235 AC: 2616 AN: 1111948

Other (OTH) AF: 0.00237 AC: 143 AN: 60380

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152284 Hom.: 0 Cov.: 31 AF XY: 0.000819 AC XY: 61 AN XY: 74474

African (AFR) AF: 0.000313 AC: 13 AN: 41556

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00196

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
10	4	-	not provided (14)
5	1	-	Fumarase deficiency (7)
3	1	-	Hereditary leiomyomatosis and renal cell cancer (4)
1	-	1	Hereditary cancer-predisposing syndrome (2)
1	-	-	FH-related disorder (1)
1	-	-	Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer (1)
-	1	-	Inherited renal cancer (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=55/45	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs367543046; hg19: chr1-241661227; COSMIC: COSV63818739;