rs760106433

Positions:

• chr1-23808283-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000191.3(HMGCL):​c.602C>A​(p.Ser201Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,804 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HMGCL NM_000191.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.97

Genes affected

HMGCL (HGNC:5005): (3-hydroxy-3-methylglutaryl-CoA lyase) The protein encoded by this gene belongs to the HMG-CoA lyase family. It is a mitochondrial enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Mutations in this gene are associated with HMG-CoA lyase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a strand (size 6) in uniprot entity HMGCL_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000191.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 1-23808283-G-T is Pathogenic according to our data. Variant chr1-23808283-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 449033.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
HMGCL	NM_000191.3	c.602C>A	p.Ser201Tyr	missense_variant	7/9	ENST00000374490.8	NP_000182.2
HMGCL	NM_001166059.2	c.389C>A	p.Ser130Tyr	missense_variant	5/7		NP_001159531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCL	ENST00000374490.8	c.602C>A	p.Ser201Tyr	missense_variant	7/9	1	NM_000191.3	ENSP00000363614.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251428 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135896

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461804 Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 30, 2022	A Homozygous missense variation in exon 7 of the HMGCL gene that results in the amino acid substitution of Tyrosine for Serine at codon 201 was detected. The observed variation lies in the BAR domain of APPL family of HMGCL protien and has previously been reported in patients affected with HMG-CoA lyase deficiency. The c.602C>A (p.Ser201Tyr) variant has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.01% in our internal database. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Feb 21, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 01, 2020

Functional analysis in E.coli found that this variant is associated with no detectable residual enzyme activity (Casals et al., 2003).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 12746442) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.89		Gain of sheet (P = 0.1451);.;
MVP		0.99
MPC		0.54
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
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: rs760106433; hg19: chr1-24134773;