1-23802508-G-C

Variant names:

• chr1-23802508-G-C
• rs1194563406
• NM_000191.3:c.933C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000191.3(HMGCL):​c.933C>G​(p.Asn311Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N311D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HMGCL NM_000191.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.46042 (below the threshold of 3.09). Trascript score misZ: 0.32928 (below the threshold of 3.09). GenCC associations: The gene is linked to 3-hydroxy-3-methylglutaric aciduria.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000191.3. 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
	HMGCL	NM_000191.3	MANE Select	c.933C>G	p.Asn311Lys	missense	Exon 9 of 9	NP_000182.2
	HMGCL	NM_001166059.2		c.720C>G	p.Asn240Lys	missense	Exon 7 of 7	NP_001159531.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCL	ENST00000374490.8	TSL:1 MANE Select	c.933C>G	p.Asn311Lys	missense	Exon 9 of 9	ENSP00000363614.3
	HMGCL	ENST00000436439.6	TSL:2	c.720C>G	p.Asn240Lys	missense	Exon 7 of 7	ENSP00000389281.2
	HMGCL	ENST00000235958.4	TSL:5	c.501C>G	p.Asn167Lys	missense	Exon 5 of 5	ENSP00000235958.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461790 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111926

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.52
Sift	Benign	0.069	T
Sift4G	Uncertain	0.038	D
Polyphen		0.071	B
Vest4		0.44
MutPred		0.55		Loss of helix (P = 0.0123)
MVP		0.96
MPC		0.22
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.51
gMVP		0.73
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1194563406; hg19: chr1-24128998;