rs719400

Variant names:

• chr1-23808231-T-C
• rs719400
• NM_000191.3:c.654A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000191.3(HMGCL):​c.654A>G​(p.Leu218Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,613,874 control chromosomes in the GnomAD database, including 672,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L218L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.92 (64921 hom., cov: 31)
  • Exomes 𝑓: 0.91 (607851 hom.)
• Consequence: HMGCL NM_000191.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.23
• Publications: 25 publications found

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]

HMGCL Gene-Disease associations (from GenCC):

• 3-hydroxy-3-methylglutaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health, ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.08).
• BP6: Variant 1-23808231-T-C is Benign according to our data. Variant chr1-23808231-T-C is described in ClinVar as Benign. ClinVar VariationId is 92602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCL	NM_000191.3	c.654A>G	p.Leu218Leu	synonymous_variant	Exon 7 of 9	ENST00000374490.8	NP_000182.2
HMGCL	NM_001166059.2	c.441A>G	p.Leu147Leu	synonymous_variant	Exon 5 of 7		NP_001159531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCL	ENST00000374490.8	c.654A>G	p.Leu218Leu	synonymous_variant	Exon 7 of 9	1	NM_000191.3	ENSP00000363614.3

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140340 AN: 152052 Hom.: 64879 Cov.: 31

Gnomad AFR AF: 0.966

Gnomad AMI AF: 0.966

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.868

Gnomad EAS AF: 0.791

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.965

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.915

Gnomad OTH AF: 0.924

GnomAD2 exomes AF: 0.902 AC: 226778 AN: 251422 AF XY: 0.900

Gnomad AFR exome AF: 0.968

Gnomad AMR exome AF: 0.894

Gnomad ASJ exome AF: 0.869

Gnomad EAS exome AF: 0.788

Gnomad FIN exome AF: 0.960

Gnomad NFE exome AF: 0.913

Gnomad OTH exome AF: 0.910

GnomAD4 exome AF: 0.912 AC: 1332356 AN: 1461704 Hom.: 607851 Cov.: 47 AF XY: 0.910 AC XY: 661880 AN XY: 727162

African (AFR) AF: 0.968 AC: 32401 AN: 33476

American (AMR) AF: 0.893 AC: 39916 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 22760 AN: 26136

East Asian (EAS) AF: 0.824 AC: 32698 AN: 39700

South Asian (SAS) AF: 0.880 AC: 75919 AN: 86252

European-Finnish (FIN) AF: 0.958 AC: 51157 AN: 53388

Middle Eastern (MID) AF: 0.940 AC: 5421 AN: 5766

European-Non Finnish (NFE) AF: 0.915 AC: 1017266 AN: 1111878

Other (OTH) AF: 0.908 AC: 54818 AN: 60390

GnomAD4 genome AF: 0.923 AC: 140444 AN: 152170 Hom.: 64921 Cov.: 31 AF XY: 0.923 AC XY: 68686 AN XY: 74392

African (AFR) AF: 0.966 AC: 40100 AN: 41522

American (AMR) AF: 0.888 AC: 13564 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 3013 AN: 3470

East Asian (EAS) AF: 0.791 AC: 4074 AN: 5150

South Asian (SAS) AF: 0.867 AC: 4186 AN: 4828

European-Finnish (FIN) AF: 0.965 AC: 10232 AN: 10608

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.915 AC: 62183 AN: 67994

Other (OTH) AF: 0.917 AC: 1937 AN: 2112

Alfa AF: 0.912 Hom.: 120854

Bravo AF: 0.920

Asia WGS AF: 0.833 AC: 2898 AN: 3478

EpiCase AF: 0.906

EpiControl AF: 0.907

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Feb 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Deficiency of hydroxymethylglutaryl-CoA lyase Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.6
DANN	Benign	0.71
PhyloP100		1.2
Mutation Taster		=92/8	polymorphism (auto)

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: rs719400; hg19: chr1-24134721; COSMIC: COSV108035619; COSMIC: COSV108035619;