NM_004483.5:c.344C>T

Variant names:

• chr16-81084543-G-A
• NM_004483.5:c.344C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004483.5(GCSH):​c.344C>T​(p.Pro115Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCSH NM_004483.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.71
• Publications: 1 publications found

Genes affected

GCSH (HGNC:4208): (glycine cleavage system protein H) Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the H protein, which transfers the methylamine group of glycine from the P protein to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH). Two transcript variants, one protein-coding and the other probably not protein-coding,have been found for this gene. Also, several transcribed and non-transcribed pseudogenes of this gene exist throughout the genome.[provided by RefSeq, Jan 2010]

GCSH Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Ambry Genetics
• multiple mitochondrial dysfunctions syndrome 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284512 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 16-81084543-G-A is Pathogenic according to our data. Variant chr16-81084543-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2506442.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004483.5. 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
	GCSH	NM_004483.5	MANE Select	c.344C>T	p.Pro115Leu	missense	Exon 4 of 5	NP_004474.2
	GCSH	NR_033249.2		n.397C>T		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSH	ENST00000315467.9	TSL:1 MANE Select	c.344C>T	p.Pro115Leu	missense	Exon 4 of 5	ENSP00000319531.3	P23434
	ENSG00000284512	ENST00000640345.1	TSL:5	c.344C>T	p.Pro115Leu	missense	Exon 4 of 6	ENSP00000492798.1	A0A1W2PS29
	ENSG00000260643	ENST00000564536.2	TSL:5	c.344C>T	p.Pro115Leu	missense	Exon 4 of 6	ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple mitochondrial dysfunctions syndrome 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.89		Loss of disorder (P = 0.0321)
MVP		0.94
MPC		1.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -9

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

Other links and lift over

hg19: chr16-81118148;