NM_001134707.2:c.2557C>T

Variant names:

• chr9-133666809-G-A
• rs1198774607
• NM_001134707.2:c.2557C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001134707.2(SARDH):​c.2557C>T​(p.Arg853Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,200 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.51

Genes affected

SARDH (HGNC:10536): (sarcosine dehydrogenase) This gene encodes an enzyme localized to the mitochondrial matrix which catalyzes the oxidative demethylation of sarcosine. This enzyme is distinct from another mitochondrial matrix enzyme, dimethylglycine dehydrogenase, which catalyzes a reaction resulting in the formation of sarcosine. Mutations in this gene are associated with sarcosinemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARDH	NM_001134707.2	c.2557C>T	p.Arg853Trp	missense_variant	Exon 20 of 21	ENST00000439388.6	NP_001128179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARDH	ENST00000439388.6	c.2557C>T	p.Arg853Trp	missense_variant	Exon 20 of 21	2	NM_001134707.2	ENSP00000403084.1
SARDH	ENST00000371872.8	c.2557C>T	p.Arg853Trp	missense_variant	Exon 20 of 21	1		ENSP00000360938.4
SARDH	ENST00000371868.5	c.907C>T	p.Arg303Trp	missense_variant	Exon 8 of 9	2		ENSP00000360934.1
SARDH	ENST00000469828.1	n.315C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456200 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 723826

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2557C>T (p.R853W) alteration is located in exon 20 (coding exon 19) of the SARDH gene. This alteration results from a C to T substitution at nucleotide position 2557, causing the arginine (R) at amino acid position 853 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;D;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.3	M;.;.;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.8	D;D;.;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.98
MutPred		0.72		Loss of MoRF binding (P = 0.1258);.;.;Loss of MoRF binding (P = 0.1258);
MVP		0.91
MPC		0.81
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.69
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: rs1198774607; hg19: chr9-136531931; COSMIC: COSV64100540;