5-132392577-G-C

Variant names:

• chr5-132392577-G-C
• rs386134223
• NM_003060.4:c.1412G>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003060.4(SLC22A5):​c.1412G>C​(p.Arg471Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005075871: "experimental evidence evaluating an impact on protein function, demonstrating undetectable carnitine transport activity when compared to Wildtype (Frigeni_2017)"". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R471L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.57
• Publications: 0 publications found

Genes affected

SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

SLC22A5 Gene-Disease associations (from GenCC):

• systemic primary carnitine deficiency disease

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

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005075871: "experimental evidence evaluating an impact on protein function, demonstrating undetectable carnitine transport activity when compared to Wildtype (Frigeni_2017)"
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132392577-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 5-132392577-G-C is Pathogenic according to our data. Variant chr5-132392577-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1456659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003060.4. 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
	SLC22A5	NM_003060.4	MANE Select	c.1412G>C	p.Arg471Pro	missense	Exon 8 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.1484G>C	p.Arg495Pro	missense	Exon 9 of 11	NP_001295051.1	O76082-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.1412G>C	p.Arg471Pro	missense	Exon 8 of 10	ENSP00000245407.3	O76082-1
	SLC22A5	ENST00000435065.7	TSL:1	c.1484G>C	p.Arg495Pro	missense	Exon 9 of 11	ENSP00000402760.2	O76082-3
	SLC22A5	ENST00000448810.6	TSL:1	n.*264G>C		non_coding_transcript_exon	Exon 8 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Renal carnitine transport defect (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.81		Loss of methylation at R471 (P = 0.0129)
MVP		0.99
MPC		0.98
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.98
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs386134223; hg19: chr5-131728269;