1-23802496-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000191.3(HMGCL):c.945C>G(p.Ser315Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HMGCL NM_000191.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.435

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Hydroxymethylglutaryl-CoA lyase, mitochondrial (size 297) in uniprot entity HMGCL_HUMAN there are 41 pathogenic changes around while only 4 benign (91%) in NM_000191.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17194244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCL	NM_000191.3	c.945C>G	p.Ser315Arg	missense_variant	9/9	ENST00000374490.8
HMGCL	NM_001166059.2	c.732C>G	p.Ser244Arg	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCL	ENST00000374490.8	c.945C>G	p.Ser315Arg	missense_variant	9/9	1	NM_000191.3	P1
HMGCL	ENST00000436439.6	c.732C>G	p.Ser244Arg	missense_variant	7/7	2
HMGCL	ENST00000235958.4	c.516C>G	p.Ser172Arg	missense_variant	5/5	5
HMGCL	ENST00000374487.6	n.1542C>G		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

This sequence change replaces serine with arginine at codon 315 of the HMGCL protein (p.Ser315Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with HMGCL-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.52	D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.13	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.015	B;.
Vest4		0.10
MutPred		0.37		Gain of MoRF binding (P = 0.0165);.;
MVP		0.80
MPC		0.14
ClinPred		0.58	D
GERP RS		-5.4
Varity_R		0.26
gMVP		0.76

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: rs1557484629; hg19: chr1-24128986; COSMIC: COSV52525456; COSMIC: COSV52525456;